On September 6, 2022 Kite, a Gilead Company (Nasdaq: GILD), reported that the European Commission (EC) has approved its CAR T-cell therapy Tecartus (brexucabtagene autoleucel) for the treatment of adult patients 26 years of age and above with relapsed or refractory (r/r) B-cell precursor acute lymphoblastic leukemia (ALL) (Press release, Kite Pharma, SEP 6, 2022, View Source [SID1234619096]).

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"This approval makes Tecartus the first and only CAR T-cell therapy indicated for this population of patients, addressing a significant unmet medical need," said Christi Shaw, CEO, Kite. "This is also the fourth indication in Europe for which a Kite cell therapy is approved, clearly demonstrating the benefits they offer to patients, especially those with limited treatment options."

ALL is an aggressive type of blood cancer; the most common form is B-cell precursor ALL. Globally, approximately 64,000 people are diagnosed with ALL each year. Half of adults living with ALL will relapse, and median overall survival (OS) with current standard-of-care treatments is approximately just eight months.

"Adults with relapsed or refractory ALL often undergo multiple treatments including chemotherapy, targeted therapy and stem cell transplant, creating a significant burden on a patient’s quality of life," said Max S. Topp, MD, professor and head of Hematology, University Hospital of Wuerzburg, Germany. "Patients in Europe now have a meaningful advancement in treatment. Tecartus has demonstrated durable responses, suggesting the potential for long-term remission and a new approach to care."

The approval is supported by data from the ZUMA-3 international multicenter, single-arm, open-label, registrational Phase 1/2 study of adult patients (≥18 years old) with relapsed or refractory ALL. This study demonstrated that 71% of the evaluable patients (n=55) achieved complete remission (CR) or CR with incomplete hematological recovery (CRi) with a median follow-up of 26.8 months. In an extended data set of all pivotal dosed patients (n=78) the median overall survival for all patients was more than two years (25.4 months) and almost four years (47 months) for responders (patients who achieved CR or CRi). Among efficacy-evaluable patients, median duration of remission (DOR) was 18.6 months.

Among the patients treated with Tecartus at the target dose (n=100) safety results were consistent with the known safety profile for Tecartus. Grade 3 or higher cytokine release syndrome (CRS) and neurologic adverse reactions occurred in 25% and 32% of patients, respectively, and were generally well managed.

About ZUMA-3

ZUMA-3 is an ongoing international multicenter (US, Canada, Europe), single arm, open label, registrational Phase 1/2 study of Tecartus in adult patients (≥18 years old) with ALL whose disease is refractory to or has relapsed following standard systemic therapy or hematopoietic stem cell transplantation. The primary endpoint is the rate of overall complete remission or complete remission with incomplete hematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints.

About Acute Lymphoblastic Leukemia

ALL is an aggressive type of blood cancer that develops when abnormal white blood cells accumulate in the bone marrow until there isn’t any room left for blood cells to form. In some cases, these abnormal cells invade healthy organs and can also involve the lymph nodes, spleen, liver, central nervous system and other organs.

About Tecartus

Please see full FDA Prescribing Information, including BOXED WARNING and Medication Guide.

Tecartus is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

Adult patients with relapsed or refractory mantle cell lymphoma (MCL).
This indication is approved under accelerated approval based on overall response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including life-threatening reactions, occurred in patients receiving Tecartus. Do not administer Tecartus to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including life-threatening reactions, occurred in patients receiving Tecartus, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Tecartus. Provide supportive care and/or corticosteroids as needed.
Tecartus is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus REMS Program.
Cytokine Release Syndrome (CRS), including life-threatening reactions, occurred following treatment with Tecartus. In ZUMA-2, CRS occurred in 92% (72/78) of patients with ALL, including ≥ Grade 3 (Lee grading system 1) CRS in 26% of patients. Three patients with ALL had ongoing CRS events at the time of death. The median time to onset of CRS was five days (range: 1 to 12 days) and the median duration of CRS was eight days (range: 2 to 63 days) for patients with ALL.. Among patients with CRS, the key manifestations (>10%) were similar in MCL and ALL and included fever (93%), hypotension (62%), tachycardia (59%), chills (32%), hypoxia (31%), headache (21%), fatigue (20%), and nausea (13%). Serious events associated with CRS included hypotension, fever, hypoxia, tachycardia, and dyspnea.

Ensure that a minimum of two doses of tocilizumab are available for each patient prior to infusion of Tecartus. Following infusion, monitor patients for signs and symptoms of CRS daily for at least seven days for patients with MCL and at least 14 days for patients with ALL at the certified healthcare facility, and for four weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

Neurologic Events, including those that were fatal or life-threatening, occurred following treatment with Tecartus. Neurologic events occurred in 81% (66/82) of patients with MCL, including ≥ Grade 3 in 37% of patients. The median time to onset for neurologic events was six days (range: 1 to 32 days) with a median duration of 21 days (range: 2 to 454 days) in patients with MCL. Neurologic events occurred in 87% (68/78) of patients with ALL, including ≥ Grade 3 in 35% of patients. The median time to onset for neurologic events was seven days (range: 1 to 51 days) with a median duration of 15 days (range: 1 to 397 days) in patients with ALL. For patients with MCL, 54 (66%) patients experienced CRS before the onset of neurological events. Five (6%) patients did not experience CRS with neurologic events and eight patients (10%) developed neurological events after the resolution of CRS. Neurologic events resolved for 119 out of 134 (89%) patients treated with Tecartus. Nine patients (three patients with MCL and six patients with ALL) had ongoing neurologic events at the time of death. For patients with ALL, neurologic events occurred before, during, and after CRS in 4 (5%), 57 (73%), and 8 (10%) of patients; respectively. Three patients (4%) had neurologic events without CRS. The onset of neurologic events can be concurrent with CRS, following resolution of CRS or in the absence of CRS.

The most common neurologic events (>10%) were similar in MCL and ALL and included encephalopathy (57%), headache (37%), tremor (34%), confusional state (26%), aphasia (23%), delirium (17%), dizziness (15%), anxiety (14%), and agitation (12%). Serious events including encephalopathy, aphasia, confusional state, and seizures occurred after treatment with Tecartus.

Monitor patients daily for at least seven days for patients with MCL and at least 14 days for patients with ALL at the certified healthcare facility and for four weeks following infusion for signs and symptoms of neurologic toxicities and treat promptly.

REMS Program: Because of the risk of CRS and neurologic toxicities, Tecartus is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus REMS Program which requires that:

Healthcare facilities that dispense and administer Tecartus must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of two doses of tocilizumab are available for each patient for infusion within two hours after Tecartus infusion, if needed for treatment of CRS.
Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer Tecartus are trained in the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).
Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis, may occur due to dimethyl sulfoxide (DMSO) or residual gentamicin in Tecartus.

Severe Infections: Severe or life-threatening infections occurred in patients after Tecartus infusion. Infections (all grades) occurred in 56% (46/82) of patients with MCL and 44% (34/78) of patients with ALL. Grade 3 or higher infections, including bacterial, viral, and fungal infections, occurred in 30% of patients with ALL and MCL. Tecartus should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Tecartus infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 6% of patients with MCL and 35% of patients with ALL after Tecartus infusion and may be concurrent with CRS. The febrile neutropenia in 27 (35%) of patients with ALL includes events of "febrile neutropenia" (11 (14%)) plus the concurrent events of "fever" and "neutropenia" (16 (21%)). In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.

In immunosuppressed patients, life-threatening and fatal opportunistic infections have been reported. The possibility of rare infectious etiologies (e.g., fungal and viral infections such as HHV-6 and progressive multifocal leukoencephalopathy) should be considered in patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Tecartus infusion. In patients with MCL, Grade 3 or higher cytopenias not resolved by Day 30 following Tecartus infusion occurred in 55% (45/82) of patients and included thrombocytopenia (38%), neutropenia (37%), and anemia (17%). In patients with ALL who were responders to Tecartus treatment, Grade 3 or higher cytopenias not resolved by Day 30 following Tecartus infusion occurred in 20% (7/35) of the patients and included neutropenia (12%) and thrombocytopenia (12%); Grade 3 or higher cytopenias not resolved by Day 60 following Tecartus infusion occurred in 11% (4/35) of the patients and included neutropenia (9%) and thrombocytopenia (6%). Monitor blood counts after Tecartus infusion.

Hypogammaglobulinemia: B cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with Tecartus. Hypogammaglobulinemia was reported in 16% (13/82) of patients with MCL and 9% (7/78) of patients with ALL. Monitor immunoglobulin levels after treatment with Tecartus and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement.

The safety of immunization with live viral vaccines during or following Tecartus treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least six weeks prior to the start of lymphodepleting chemotherapy, during Tecartus treatment, and until immune recovery following treatment with Tecartus.

Secondary Malignancies may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Tecartus infusion. Advise patients to refrain from driving and engaging in hazardous activities, such as operating heavy or potentially dangerous machinery, during this period.

Adverse Reactions: The most common non-laboratory adverse reactions (≥ 20%) were fever, cytokine release syndrome, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting. The most common serious adverse reactions (≥ 2%) were cytokine release syndrome, febrile neutropenia, hypotension, encephalopathy, fever, infection with pathogen unspecified, hypoxia, tachycardia, bacterial infections, respiratory failure, seizure, diarrhea, dyspnea, fungal infections, viral infections, coagulopathy, delirium, fatigue, hemophagocytic lymphohistiocytosis, musculoskeletal pain, edema, and paraparesis.

On September 6, 2022 MEI Pharma, Inc. (NASDAQ: MEIP), a late-stage pharmaceutical company focused on advancing new therapies for cancer, reported its participation in the H.C. Wainwright 24th Annual Global Investment Conference 2022 (Press release, MEI Pharma, SEP 6, 2022, View Source [SID1234619095]). The company will present a company overview and business update available for on-demand listening starting Monday, September 12, 2022, 7:00 a.m. Eastern Time that will be archived for 90 days.

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The presentation can be accessed via the Events & Presentations page of the Investors section of MEI Pharma’s website at View Source An archived replay of the webcast will be available on MEI Pharma’s website for at least 30 days after the live event concludes.

On September 6, 2022 MAIA Biotechnology, Inc. (NYSE American: MAIA) ("MAIA," "the Company"), a clinical-stage biopharmaceutical company developing targeted immunotherapies for cancer, reported that it will present the design of its ongoing THIO-101 trial at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022, being held from September 9th to 13th in Paris, France (Press release, MAIA Biotechnology, SEP 6, 2022, View Source [SID1234619094]).

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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THIO is a telomere-targeting agent currently in clinical development to evaluate its activity in non-small cell lung cancer (NSCLC). The first patient was enrolled in the THIO-101 study in July 2022 in Australia.

Details of the presentation are as follows:

Abstract title: A Phase 2, Multicenter, Open-Label, Dose-Finding Study Evaluating THIO Sequenced with Cemiplimab in Patients with Advanced NSCLC – A Trial in Progress
Abstract number: 1193
Session title: Trial in Progress (TiP)
Presentation date: Monday, September 12
The full abstract is available on the ESMO (Free ESMO Whitepaper) Congress 2022 website.

About THIO

THIO (6-thio-dG or 6-thio-2’-deoxyguanosine) is a telomere-targeting agent currently in clinical development to evaluate its activity in non-small cell lung cancer (NSCLC), in sequential administration with cemiplimab (Libtayo), a PD-1 inhibitor developed by Regeneron. Telomeres play a fundamental role in the survival of cancer cells and their resistance to current therapies. THIO is being developed as a second or higher line of treatment for NSCLC for patients that have progressed beyond the standard-of-care regimen of existing checkpoint inhibitors.

On September 6, 2022 Daiichi Sankyo (TSE: 4568) reported to make bold strides in oncology with the presentation of new clinical research across its innovative DXd antibody drug conjugate (ADC) portfolio in a broad range of cancers including lung, breast, gastric, esophageal and prostate at the 2022 European Society for Medical Oncology (#ESMO22) Congress to be held September 9 to 13, 2022 (Press release, Daiichi Sankyo, SEP 6, 2022, https://www.businesswire.com/news/home/20220902005314/en/Daiichi-Sankyo-Continues-to-Make-Bold-Strides-in-Oncology-Across-DXd-ADC-Portfolio-at-2022-ESMO [SID1234619093]).

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Late-breaking results will be featured from an interim analysis of the DESTINY-Lung02 phase 2 trial in patients with previously treated HER2 mutant metastatic non-small cell lung cancer (NSCLC), which formed the basis for the recent accelerated approval in the U.S. of ENHERTU (trastuzumab deruxtecan) in this tumor type. Additionally, updated data from both the HER2 mutant and HER2 overexpressing cohorts of the DESTINY-Lung01 phase 2 trial also will be presented.

A proffered paper presentation of extended follow-up data from a phase 1/2 trial of DS-7300 in patients with heavily pretreated metastatic solid tumors including extensive-stage small cell lung cancer, castration-resistant prostate cancer, esophageal squamous cell carcinoma and squamous NSCLC will be highlighted.

"Following the recent first-of-its-kind approvals of ENHERTU in the U.S. in patients with previously-treated metastatic HER2 low breast cancer and HER2 mutant non-small cell lung cancer, we are proud to continue to report new data across our DXd ADC portfolio in several different tumor types at this year’s ESMO (Free ESMO Whitepaper)," said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. "We look forward to sharing results from the DESTINY-Lung02 trial of ENHERTU for the first time along with updated data from DS-7300, our B7-H3 directed ADC, in patients with certain types of lung, esophageal and prostate cancer."

Other ENHERTU data to be featured at ESMO (Free ESMO Whitepaper) include a proffered paper presentation on patient-reported outcomes from the DESTINY-Breast04 phase 3 trial, a poster presentation reporting subgroup analyses of the DESTINY-Breast03 phase 3 trial, and a mini-oral presentation of updated data from the DESTINY-Gastric02 phase 2 trial.

Several trial-in-progress presentations also will provide an overview of ongoing clinical trials across the DXd ADC portfolio including the TROPION-Breast01 phase 3 trial of datopotamab deruxtecan, the HERTHENA-Lung02 phase 3 trial of patritumab deruxtecan and a phase 2 trial of DS-7300. Highlights of Daiichi Sankyo DXd ADC data at 2022 ESMO (Free ESMO Whitepaper) include:

Presentation Title

Author

Abstract

Presentation

ENHERTU (trastuzumab deruxtecan/T-DXd; HER2 directed ADC)

Lung

Trastuzumab deruxtecan in patients with HER2 mutated metastatic non-small cell lung cancer: interim results from the phase 2 DESTINY-Lung02 trial

Y. Goto

LBA55

Late-Breaking Presentation

Mini Oral Presentation

Sunday, September 11, 2022

10:15 – 11:45 CEST

Trastuzumab deruxtecan in patients with HER2 overexpressing metastatic non-small cell lung cancer: results from the DESTINY-Lung01 trial

E.F. Smit

975P

Poster Presentation

Monday, September 12, 2022

12:00 – 13:00 CEST

Phase 2 trial of trastuzumab deruxtecan in patients with HER2 mutated metastatic non–small cell lung cancer: registrational data from DESTINY-Lung01

B.T. Li

976P

Poster Presentation

Monday, September 12, 2022

12:00 – 13:00 CEST

Breast

Patient-reported outcomes from DESTINY-Breast04, a randomized phase 3 study of trastuzumab deruxtecan vs treatment of physician’s choice in patients with HER2 low metastatic breast cancer

N.T. Ueno

217OP

Proffered Poster Presentation

Sunday, September 11, 2022

9:30 – 9:40 CEST

Subgroup analysis by disease history and prior treatments of patients with HER2 positive metastatic breast cancer from DESTINY-Breast03, a randomized phase 3 study of trastuzumab deruxtecan vs trastuzumab emtansine

J. Cortes

236P

Poster Presentation

Saturday, September 10, 2022

12:00 – 13:00 CEST

Unraveling the mechanism of action and resistance to trastuzumab deruxtecan (T-DXd): biomarker analyses from patients from DAISY trial

F. Mosele

LBA72

Late-Breaking Presentation

Mini Oral Presentation

Sunday, September 11, 2022

14:45 – 16:15 CEST

Antitumor activity of trastuzumab deruxtecan in patients with metastatic breast cancer and brain metastases from DAISY trial

N. Epaillard

260P

Poster Presentation

Saturday, September 10, 2022

12:00 – 13:00 CEST

Gastric

Updated analysis of DESTINY-Gastric02: a phase 2 single-arm trial of trastuzumab deruxtecan in Western patients with HER2 positive unresectable/metastatic gastric/gastroesophageal junction cancer who progressed on or after trastuzumab-containing regimen

G. Ku

1205MO

Mini Oral Presentation

Saturday, September 10, 2022

15:55 – 16:00 CEST

DS-7300 (B7-H3 Directed ADC)

Lung

Esophageal

Prostate

B7-H3 DXd antibody drug conjugate shows durable antitumor activity in advanced solid tumors: extended follow-up of a phase 1/2 study

T. Doi

453O

Proffered Paper Presentation

Saturday, September 10, 2022

10:35 – 10:45 CEST

Lung

Phase 2, multicenter, randomized, open-label study of DS-7300 in participants with previously treated extensive-stage small cell lung cancer

L. Paz-Ares

1550TiP

Poster Presentation

Saturday, September 10, 2022

13:00 – 13:20 CEST

Datopotamab Deruxtecan (Dato-DXd; TROP2 directed ADC)

Lung

ORCHARD platform study: osimertinib + datopotamab deruxtecan (Dato-DXd) cohort in patients (pts) with advanced NSCLC (aNSCLC) who have progressed on first-line (1L) osimertinib

A.J. de Langen

1188TiP

Poster Presentation

Monday, September 12, 2022

12:00 – 13:00 CEST

Breast

Datopotamab deruxtecan, a TROP2 antibody drug conjugate vs investigators’ choice of chemotherapy in patients with previously treated, inoperable or metastatic hormone receptor positive, HER2 negative breast cancer: TROPION-Breast01

A. Bardia

274TiP

Poster Presentation

Saturday, September 10, 2022

16:20 – 16:40 CEST

Patritumab Deruxtecan (HER3-DXd; HER3 directed ADC)

Lung

HERTHENA-Lung02: a randomized phase 3 study of patritumab deruxtecan vs platinum-based chemotherapy in locally advanced or metastatic EGFR mutated non-small cell lung cancer after progression on a 3rd-generation EGFR TKI

T. Mok

1195TiP

Poster Presentation

Monday, September 12, 2022

12:00 – 13:00 CEST

Pharmacokinetics, efficacy, and safety of patritumab deruxtecan in EGFR inhibitor-resistant, EGFR mutated non-small cell lung cancer

H. Yu

1190TiP

Poster Presentation

Monday, September 12, 2022

12:00 – 13:00 CEST

Breast

TOT-HER3 SOLTI trial: a window of opportunity trial of patritumab deruxtecan in patients with treatment-naïve early breast cancer

M. Olivera

202TiP

Poster Presentation

Saturday, September 10, 2022

12:00 – 13:00 CEST

Increased membrane HER3 expression in brain metastases compared to primary tumors in breast cancer

S. Kusuhara

264P

Poster Presentation

Saturday, September 10, 2022

12:00 – 13:00 CEST

About the DXd ADC Portfolio of Daiichi Sankyo

The DXd ADC portfolio of Daiichi Sankyo currently consists of five ADCs in clinical development across multiple types of cancer. The company’s three lead ADCs include ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca; and patritumab deruxtecan (HER3-DXd), a HER3 directed ADC. Two additional ADCs including DS-7300 (B7-H3) and DS-6000 (CDH6) are being developed in part through a strategic research collaboration with Sarah Cannon Research Institute.

Each ADC is designed using Daiichi Sankyo’s proprietary DXd ADC technology to target and deliver cytotoxic payload inside cancer cells that express a specific cell surface antigen. Each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

ENHERTU is not approved outside the U.S. for the treatment of patients with metastatic HER2 low breast cancer or HER2 mutant NSCLC.

Patritumab deruxtecan, datopotamab deruxtecan, DS-7300 and DS-6000 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.

U.S. Important Safety Information for ENHERTU

Indications

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

Unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either:
– In the metastatic setting, or
– In the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy

Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy

Unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy

This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen
WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY
Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.
Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.
Contraindications
None.

Warnings and Precautions
Interstitial Lung Disease / Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)
In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of patients treated with ENHERTU. Median time to first onset was 5 months (range: 0.9 to 23).

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21).

Neutropenia
Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by one level.

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)
In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Sixteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 664). Febrile neutropenia was reported in 1.1% of patients.

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

Left Ventricular Dysfunction
Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)
In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.6% of patients, of which 0.4% were Grade 3.

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF.

Embryo-Fetal Toxicity
ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose of ENHERTU.

Additional Dose Modifications
Thrombocytopenia
For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then reduce dose by one level.

Adverse Reactions
Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)
The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 984 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04, and DESTINY-Lung02. Among these patients 65% were exposed for >6 months and 39% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (71%), decreased hemoglobin (66%), decreased neutrophil count (65%), decreased lymphocyte count (55%), fatigue (54%), decreased platelet count (47%), increased aspartate aminotransferase (48%), vomiting (44%), increased alanine aminotransferase (42%), alopecia (39%), increased blood alkaline phosphatase (39%), constipation (34%), musculoskeletal pain (32%), decreased appetite (32%), hypokalemia (28%), diarrhea (28%), and respiratory infection (24%).

HER2-Positive Metastatic Breast Cancer
DESTINY-Breast03
The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg intravenously every three weeks in DESTINY-Breast03. The median duration of treatment was 14 months (range: 0.7 to 30).

Serious adverse reactions occurred in 19% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (one patient each).

ENHERTU was permanently discontinued in 14% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 44% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis. Dose reductions occurred in 21% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, neutropenia, and fatigue.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (74%), decreased neutrophil count (70%), increased aspartate aminotransferase (67%), decreased hemoglobin (64%), decreased lymphocyte count (55%), increased alanine aminotransferase (53%), decreased platelet count (52%), fatigue (49%), vomiting (49%), increased blood alkaline phosphatase (49%), alopecia (37%), hypokalemia (35%), constipation (34%), musculoskeletal pain (31%), diarrhea (29%), decreased appetite (29%), respiratory infection (22%), headache (22%), abdominal pain (21%), increased blood bilirubin (20%), and stomatitis (20%).

HER2-Low Metastatic Breast Cancer
DESTINY-Breast04
The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg intravenously every 3 weeks in DESTINY-Breast04. The median duration of treatment was 8 months (range: 0.2 to 33) for patients who received ENHERTU.

Serious adverse reactions occurred in 28% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4% of patients including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each).

ENHERTU was permanently discontinued in 16% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 39% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia. Dose reductions occurred in 23% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (70%), decreased hemoglobin (64%), decreased neutrophil count (64%), decreased lymphocyte count (55%), fatigue (54%), decreased platelet count (44%), alopecia (40%), vomiting (40%), increased aspartate aminotransferase (38%), increased alanine aminotransferase (36%), constipation (34%), increased blood alkaline phosphatase (34%), decreased appetite (32%), musculoskeletal pain (32%), diarrhea (27%), and hypokalemia (25%).

Unresectable or Metastatic HER2-Mutant NSCLC (5.4 mg/kg)
DESTINY-Lung02 evaluated two dose levels (5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); however, only the results for the recommended dose of 5.4 mg/kg intravenously every 3 weeks are described below due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis.

The safety of ENHERTU was evaluated in 101 patients with unresectable or metastatic HER2-mutant NSCLC who received ENHERTU 5.4 mg/kg intravenously every three weeks in DESTINY‑Lung02. Nineteen percent of patients were exposed for >6 months.

Serious adverse reactions occurred in 30% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, thrombocytopenia, dyspnea, nausea, pleural effusion, and increased troponin I. Fatality occurred in 1 patient with suspected ILD/pneumonitis (1%).

ENHERTU was permanently discontinued in 8% of patients. Adverse reactions which resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, diarrhea, hypokalemia, hypomagnesemia, myocarditis, and vomiting. Dose interruptions of ENHERTU due to adverse reactions occurred in 23% of patients. Adverse reactions which required dose interruption (>2%) included neutropenia and ILD/pneumonitis. Dose reductions due to an adverse reaction occurred in 11% of patients.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (61%), decreased white blood cell count (60%), decreased hemoglobin (58%), decreased neutrophil count (52%), decreased lymphocyte count (43%), decreased platelet count (40%), decreased albumin (39%), increased aspartate aminotransferase (35%), increased alanine aminotransferase (34%), fatigue (32%), constipation (31%), decreased appetite (30%), vomiting (26%), increased alkaline phosphatase (22%), and alopecia (21%).

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg every 3 weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) for patients who received ENHERTU.

Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%).

ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and hypokalemia. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (75%), decreased white blood cell count (74%), decreased neutrophil count (72%), decreased lymphocyte count (70%), decreased platelet count (68%), nausea (63%), decreased appetite (60%), increased aspartate aminotransferase (58%), fatigue (55%), increased blood alkaline phosphatase (54%), increased alanine aminotransferase (47%), diarrhea (32%), hypokalemia (30%), vomiting (26%), constipation (24%), increased blood bilirubin (24%), pyrexia (24%), and alopecia (22%).

Use in Specific Populations

Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months after the last dose of ENHERTU.
Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.
Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.
Geriatric Use: Of the 883 patients with breast cancer treated with ENHERTU 5.4 mg/kg, 22% were ≥65 years and 3.6% were ≥75 years. No overall differences in efficacy within clinical studies were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (60%) as compared to younger patients (48%). Of the 101 patients with unresectable or metastatic HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, 40% were ≥65 years and 8% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were ≥65 years and 14% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.
Renal Impairment: A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min).
Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).

On September 6, 2022 Guardant Health, Inc. (Nasdaq: GH), a leading precision oncology company, reported that new data from its portfolio of blood tests will be presented at the 2022 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, September 9-13 in Paris, France (Press release, Guardant Health, SEP 6, 2022, View Source [SID1234619091]). Among the seven abstracts are an oral presentation and posters highlighting the use of Guardant Health’s blood tests and real-world evidence dataset to advance cancer therapy trials, predict and monitor patient response to therapy, and identify genomic mechanisms of acquired resistance to cancer therapy.

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"We look forward to sharing new data at ESMO (Free ESMO Whitepaper) demonstrating the utility of our blood tests to increase the understanding of potential new biomarker targets and the mechanisms of therapy resistance in patients with cancer," said Helmy Eltoukhy, Guardant Health co-CEO. "The data from retrospective and real-world analyses show how comprehensive genomic profiling tests provide critical insights at every step of a patient’s treatment journey, and ultimately contribute to the development of more effective therapies and improved patient outcomes."

Full List of Guardant Health Presentations

GuardantOMNI

Genomic mechanisms of acquired resistance of patients (pts) with BRAF V600E mutant (mt) metastatic colorectal cancer (mCRC) treated in the BEACON study (Oral Presentation 316O)
Interim biomarker analysis of a phase 1b/2 study of anti-TIGIT etigilimab (MPH313) and nivolumab in subjects with select locally advanced or metastatic solid tumors (ACTIVATE) (Presentation 111P)
Clinical potential of circulating tumor DNA (ctDNA)–based molecular response (MR) and baseline blood-based tumor mutational burden (bTMB) for monitoring response to first-line (1L) chemoimmunotherapy in advanced squamous non-small cell lung cancer (sqNSCLC) (Presentation 1092P)
Early decreases in KRAS mutant allele frequency (MAF) predicts clinical benefit to the PLK1 inhibitor onvansertib in combination with FOLFIRI/bev in 2L treatment of metastatic colorectal carcinoma (mCRC) (Presentation 397P)
The PLK1 inhibitor onvansertib overcomes irinotecan resistance in RAS-mutated (mRAS) metastatic colorectal cancer (mCRC) in vivo and in patients (pts) (Presentation 366P)
Guardant360

Resistance mechanisms to lorlatinib or crizotinib in treatment-naive patients (pts) with ALK+ advanced non-small cell lung cancer (NSCLC) (Presentation 1008P)
GuardantINFORM

Real-world outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and tumors with androgen receptor (AR) 878/875 mutations (Presentation 1407P)
The full abstracts are available on the official ESMO (Free ESMO Whitepaper) 2022 website.