On September 17, 2021 Innovent Biologics, Inc. ("Innovent", HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of cancer, metabolic, autoimmune and other major diseases, reported the interim analysis results of the Phase 3 ORIENT-16 study evaluating sintilimab in combination with chemotherapy compared to chemotherapy alone for the first-line treatment of advanced or metastatic gastric or gastroesophageal junction adenocarcinoma in an oral presentation at the ESMO (Free ESMO Whitepaper) (European Society for Medical Oncology) Congress 2021 (Abstract # LBA53) (Press release, Innovent Biologics, SEP 17, 2021, View Source [SID1234587908]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

As of the June 20, 2021 data cutoff date for the interim analysis, 650 patients have been enrolled. Sintilimab in combination with chemotherapy (oxaliplatin and capecitabine) demonstrated superior overall survival (OS) compared to placebo plus chemotherapy, with a 34.0% reduction in the risk of death (HR 0.660; 95%CI, 0.505-0.864; p=0.0023) and a 5.5-month improvement in median OS (18.4 months vs. 12.9 months) in patients with CPS ≥5, and 23.4% reduction in the risk of death and a 2.9-month improvement in mOS (15.2 months vs. 12.3 months) in all randomized patients (the ITT population). The OS benefits were consistent in all prespecified subgroup analyses. The safety profile of sintilimab in this study was consistent with that observed in previously reported studies of sintilimab, and no additional safety signals were identified for the combination of sintilimab and chemotherapy.

The principal investigator of the ORIENT-16 study, Prof. Jianming Xu from the Fifth Medical Center of People’s Liberation Army General Hospital, stated, "ORIENT-16 is the first Phase 3 clinical trial in China to demonstrate an anti-PD-1 antibody in combination with chemotherapy significantly prolonged overall survival in the first-line treatment of advanced gastric cancer. Gastric cancer is one of the most common malignant tumor types globally and nearly half of all cases are diagnosed in China. The prognosis of advanced gastric cancer is very poor. The results of the ORIENT-16 study have the potential to bring a new treatment option to people with gastric cancer."

Dr. Zhou Hui, Senior Vice President of Innovent, stated, "While immunotherapy has greatly changed the treatment paradigm for many malignancies, it has not yet in gastric cancer. The treatment options for advanced gastric cancer are very limited and the ORIENT-16 study aimed to help address this unmet medical need. These results are very encouraging and confirmed the clinical value of sintilimab plus chemotherapy in the first-line treatment of advanced gastric cancer. We are grateful for all the contributions made by every investigator and patient in this study, and we hope that sintilimab can become a new treatment option for people with gastric cancer. Innovent planned to file a supplemental new drug application to the National Medical Products Administration (NMPA) in China based on the results of interim analysis. Up until now, sintilimab has demonstrated improved survival in the first-line treatment of five major types of cancer – nonsquamous non-small cell lung cancer, squamous non-small cell lung cancer, hepatocellular carcinoma, esophageal squamous cell carcinoma, and gastric cancer."

About the ORIENT-16 Study

ORIENT-16 is a randomized, double-blind, multicenter Phase 3 clinical study evaluating sintilimab in combination with chemotherapy (oxaliplatin and capecitabine), compared to placebo in combination with chemotherapy, for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma (ClinicalTrials.gov, NCT03745170). The primary endpoint was overall survival, in all randomized and in PD-L1 positive patients.

About Gastric Cancer

Gastric cancer is one of the most common malignant tumor types worldwide. According to GLOBOCAN estimates, there were approximately one million new cases and 769,000 new deaths of gastric cancer in 2020, making it the fifth most common cancer and third leading cause of cancer death globally. About half of all gastric cancer cases occurred in East Asia, mainly in China. The first-line treatment of advanced gastric cancer remains limited. Currently, the five-year survival rate of advanced or metastatic gastric cancer ranges from 5 to 20 percent, and the median overall survival is approximately one year.

About Sintilimab

Sintilimab, marketed as TYVYT (sintilimab injection) in China, is an innovative PD-1 inhibitor with global quality standards jointly developed by Innovent and Eli Lilly and Company. Sintilimab is an immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1 / PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells. Innovent is currently conducting more than 20 clinical studies of sintilimab to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical trials.

In China, sintilimab has been approved for four indications, including:

The treatment of relapsed or refractory classic Hodgkin’s lymphoma after two lines or later of systemic chemotherapy
In combination with pemetrexed and platinum chemotherapy, for the first-line treatment of nonsquamous non-small cell lung cancer
In combination with gemcitabine and platinum chemotherapy, for the first-line treatment of squamous non-small cell lung cancer
In combination with BYVASDA (bevacizumab biosimilar injection) for the first-line treatment of hepatocellular carcinoma
Additionally, Innovent currently has a regulatory submission under review in China for sintilimab for the second-line treatment of squamous non-small cell lung cancer.

Innovent also has three clinical studies of sintilimab that have met their primary endpoints:

In combination with cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil for the first-line treatment of esophageal squamous cell carcinoma
In combination with oxaliplatin and capecitabine for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma
The second-line treatment of esophageal squamous cell carcinoma
In May 2021, the U.S. FDA accepted for review the Biologics License Application (BLA) for sintilimab in combination with pemetrexed and platinum chemotherapy for the first-line treatment of nonsquamous non-small cell lung cancer.

Sintilimab was included in China’s National Reimbursement Drug List (NRDL) in 2019 as the first PD-1 inhibitor and the only PD-1 included in the list in that year.

On September 17, 2021 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high quality medicines for the treatment of cancer, metabolic, autoimmune and other major diseases, reported that the interim analysis results of the Phase 3 ORIENT-15 study evaluating sintilimab in combination with chemotherapy for the first-line treatment of esophageal squamous cell carcinoma (ESCC) were released today in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 (Abstract # LBA52) (Press release, Innovent Biologics, SEP 17, 2021, View Source [SID1234587907]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

All endpoints of ORIENT-15 were met at the interim analysis. As of the April 9, 2021 data cutoff, 659 patients were randomly assigned and received treatment. Sintilimab plus chemotherapy (cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil [5-FU]) resulted in a superior median overall survival (mOS) over placebo plus chemotherapy in all randomized patients (the ITT population) (16.7 vs 12.5 months, respectively; HR 0.628; P<0.0001) and in PD-L1 positive patients (defined as combined positive score [CPS] ≥10) (17.2 vs 13.6 months, respectively; HR 0.638; P=0.0018). Sintilimab plus chemotherapy significantly improved median progression-free survival (mPFS) in all randomized patients (7.2 vs 5.7 months, respectively; HR 0.558; P<0.0001) and in PD-L1 positive patients (8.3 vs 6.4 months, respectively; HR 0.580; P<0.0001). The safety profile of sintilimab in this study was consistent with that observed in previously reported studies of sintilimab, and no additional safety signals were identified for the combination of sintilimab and chemotherapy.

The principal investigator of the ORIENT-15 study, Prof. Shen Lin from Peking University Cancer Hospital and Institute, stated, "More than half of new and fatal cases of esophageal cancer in the world occur in China every year. Esophageal cancer is the fifth most commonly diagnosed cancer and the fourth leading cause of death from cancer in China, and squamous cell carcinoma is the predominant histologic type. The treatment options for locally advanced or metastatic ESCC are limited and represent a significant unmet clinical need. The ORIENT-15 results suggest that sintilimab in combination with chemotherapy may represent a first-line treatment option for patients with advanced or metastatic ESCC."

Dr. Hui Zhou, Senior Vice President of Innovent, stated, "We thank the investigators and study team for their joint effort and, most importantly, we would like to express our sincere gratitude to all the patients who participated in the ORIENT-15 study. We have submitted an application to the National Medical Products Administration (NMPA) of China in early September based on these results, and hope that sintilimab plus chemotherapy can become a first-line treatment option for ESCC patients in the near future ."

About the ORIENT-15 Study

ORIENT-15 is a global randomized, double-blind, multicenter Phase 3 clinical study evaluating sintilimab in combination with chemotherapy (cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil [5-FU]), compared to placebo in combination with chemotherapy, for the first-line treatment of unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ClinicalTrials.gov, NCT03748134). At the time of interim analysis, a total of 659 eligible patients (of the planned 676 estimated participants) were enrolled and randomly assigned into the experimental group or control group in a 1:1 ratio. The primary endpoints were overall survival (OS) in all randomized patients and OS in PD-L1 positive (defined as CPS ≥10) patients.

About Esophageal Squamous Cell Carcinoma (ESCC)

Esophageal cancer (EC) is one of the most common malignant tumors worldwide that begins in the inner layer (mucosa) of the esophagus, which connects the throat to the stomach. Based on GLOBOCAN 2020 estimates, approximately 600,000 new cases of esophageal cancer are diagnosed and approximately 540,000 deaths result from the disease worldwide each year. Esophageal cancer is the seventh most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide. More than half of new and fatal cases of esophageal cancer in the world occur in China. In China, it is estimated there were approximately 320,000 new cases of esophageal cancer diagnosed and approximately 300,000 deaths resulting from the disease in 2020. Esophageal cancer is the fifth most commonly diagnosed cancer and the fourth leading cause of death from cancer in China, where it has a five-year survival rate of only 30%. In the US, it is estimated there were approximately 18,000 new cases of esophageal cancer diagnosed and approximately 16,000 deaths resulting from the disease in 2020. The five-year survival rate of esophageal cancer is only 20% in the US.

The two main types of esophageal cancer are squamous cell carcinoma (SCC) and adenocarcinoma. In China, SCC is the predominant histologic type, accounting for more than 90% of all esophageal cancer. In western countries, SCC is approximately 25% of all esophageal cancer. In the past first-line standard systemic therapy was chemotherapy based on platinum drugs for unresectable locally advanced, recurrent or metastatic ESCC. Pembrolizumab has been approved as first-line treatment in combination with chemotherapy.

About Sintilimab

Sintilimab, marketed as TYVYT (sintilimab injection) in China, is an innovative PD-1 inhibitor with global quality standards jointly developed by Innovent and Eli Lilly and Company. Sintilimab is an immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1 / PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells. Innovent is currently conducting more than 20 clinical studies of sintilimab to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical trials.

In China, sintilimab has been approved for four indications, including:

The treatment of relapsed or refractory classic Hodgkin’s lymphoma after two lines or later of systemic chemotherapy
In combination with pemetrexed and platinum chemotherapy, for the first-line treatment of nonsquamous non-small cell lung cancer
In combination with gemcitabine and platinum chemotherapy, for the first-line treatment of squamous non-small cell lung cancer
In combination with BYVASDA (bevacizumab biosimilar injection) for the first-line treatment of hepatocellular carcinoma
Additionally, Innovent currently has a regulatory submission under review in China for sintilimab for the second-line treatment of squamous non-small cell lung cancer.

Innovent also has three clinical studies of sintilimab that have met their primary endpoints:

In combination with cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil for the first-line treatment of esophageal squamous cell carcinoma
In combination with oxaliplatin and capecitabine for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma
The second-line treatment of esophageal squamous cell carcinoma
In May 2021, the U.S. FDA accepted for review the Biologics License Application (BLA) for sintilimab in combination with pemetrexed and platinum chemotherapy for the first-line treatment of nonsquamous non-small cell lung cancer.

Sintilimab was included in China’s National Reimbursement Drug List (NRDL) in 2019 as the first PD-1 inhibitor and the only PD-1 included in the list in that year.

On September 17, 2021 BeiGene (NASDAQ: BGNE; HKEX: 06160) reported the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion, recommending approval of BRUKINSA (zanubrutinib) for the treatment of adult patients with Waldenström’s macroglobulinemia (WM) who have received at least one prior therapy or first-line treatment for patients unsuitable for chemo-immunotherapy (Press release, BeiGene, SEP 17, 2021, View Source [SID1234587906]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

"The ASPEN trial demonstrated that BRUKINSA provided deep and durable responses and offered substantial improvements in safety and tolerability over standard therapy. Patients in Europe with WM may soon have a new treatment option that can offer improved outcomes."

"Bruton’s tyrosine kinase (BTK) inhibitors have emerged as a promising treatment for WM, yet treatment discontinuation due to lack of response or side effects remains a concern," said Prof. Christian Buske, Medical Director at the University Hospital Ulm, Germany, and a trial investigator of the ASPEN study. "The ASPEN trial demonstrated that BRUKINSA provided deep and durable responses and offered substantial improvements in safety and tolerability over standard therapy. Patients in Europe with WM may soon have a new treatment option that can offer improved outcomes."

The positive CHMP opinion is based on results from the randomized, Phase 3 ASPEN clinical trial, evaluating BRUKINSA compared to ibrutinib in patients with relapsed or refractory (R/R) or treatment-naïve (TN) WM who are unsuitable for chemo-immunotherapy. Based on the modified Sixth International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) response criteria (Treon 2015), the combined complete response (CR) +VGPR rate in the overall intention-to-treat (ITT) population was 28.4% with BRUKINSA (95% CI: 20, 38), compared to 19.2% with ibrutinib (95% CI: 12, 28). While this difference was not statistically significant, BRUKINSA did achieve numerically higher VGPR rates and trends towards increased response quality.1

BRUKINSA demonstrated a more favorable safety profile compared to ibrutinib with lower frequency of certain adverse events, including atrial fibrillation or flutter (2.0% vs. 15.3%) minor bleeding (48.5% vs 59.2%) and major hemorrhage (5.9% vs 9.2%).1 Of the 101 patients with WM treated with BRUKINSA, four percent of patients discontinued due to adverse events, and adverse events leading to dose reduction occurred in 14% of patients.

"The positive CHMP opinion reflects BRUKINSA’s potential role in the WM therapeutic landscape as a selective inhibitor designed to deliver sustained and continuous inhibition of BTK, offering patients the potential for reduced frequency of certain cardiovascular events like atrial fibrillation compared to ibrutinib, and underscores our bold approach to R&D," said Jane Huang, M.D., Chief Medical Officer, Hematology, at BeiGene. "We are committed to advancing the global registration of BRUKINSA and, if approved, believe it will become the preferred BTK inhibitor for patients with WM."

"We have a strong team in Europe who are excited for the opportunity to further work with the many investigators who have participated in BRUKINSA trials conducted in Europe to-date. Looking to the future, we have built a team in Europe and they are poised to help patients access BRUKINSA following its expected approval," said Gerwin Winter, Senior Vice President, Head of Commercial, Europe, at BeiGene. "We look forward to continuing our work with the European health authorities to bring BRUKINSA to patients living with this rare, incurable blood cancer."

Following the CHMP positive opinion, the European Commission will consider BeiGene’s marketing application, with a final decision expected within 67 days of receipt of the CHMP opinion. The decision will be applicable to all 27 member states of the EU plus Iceland and Norway.

About Waldenström’s Macroglobulinemia

WM is a rare lymphoma representing approximately one percent of all non-Hodgkin’s lymphomas and typically progresses slowly after diagnosis.2 The disease usually affects older adults and is primarily found in the bone marrow, although lymph nodes and the spleen may be involved.3 Throughout Europe, the estimated incidence rate of WM is approximately seven for every one million men and four for every one million women.4

About the ASPEN trial

The Phase 3 randomized, open-label, multicenter ASPEN clinical trial (NCT03053440) evaluated zanubrutinib versus ibrutinib in people with relapsed or refractory (R/R) or treatment-naïve (TN) WM. The primary objective was to establish superiority of zanubrutinib compared to ibrutinib as demonstrated by the proportion of people achieving complete response (CR) or very good partial response (VGPR). Secondary endpoints included major response rate, duration of response and progression-free survival, and safety, measured by incidence, timing and severity of treatment-emergent adverse events. The pre-specified analysis populations for the trial included the overall population (n=201) and R/R patients (n=164). Exploratory endpoints included quality of life measures.

The study includes two cohorts, a randomized cohort (cohort 1) consisting of 201 patients with a MYD88 mutation (MYD88MUT) and a non-randomized cohort (cohort 2) in which 28 patients with MYD88 wild-type (MYD88WT) received zanubrutinib because they have historically responded poorly to ibrutinib therapy.

The randomized cohort 1 enrolled 102 patients (including 83 relapsed or refractory (R/R) patients and 19 TN (patients) in the zanubrutinib arm and 99 patients (including 81 R/R patients and 18 TN patients) in the ibrutinib arm. Patients in the zanubrutinib arm were assigned to receive zanubrutinib 160 mg twice daily (BID) and patients in the ibrutinib arm received 420 mg of ibrutinib once daily (QD).

Results of cohort 2 were previously presented at the 24th Congress of European Hematology Association (EHA) (Free EHA Whitepaper) and showed an overall response rate (ORR) of 80.8%, a major response rate (MRR; partial response or better) of 53.8% and a VGPR rate of 23.1%.

About BRUKINSA

BRUKINSA is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by BeiGene scientists that is currently being evaluated globally in a broad clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. Because new BTK is continuously synthesized, BRUKINSA was specifically designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared to other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease relevant tissues.

BRUKINSA is approved in the following indications and regions:

For the treatment of mantle cell lymphoma (MCL) in adult patients who have received at least one prior therapy (United States, November 2019)*;
For the treatment of MCL in adult patients who have received at least one prior therapy (China, June 2020)**;
For the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adult patients who have received at least one prior therapy (China, June 2020)**;
For the treatment of relapsed or refractory MCL (United Arab Emirates, February 2021);
For the treatment of Waldenström’s macroglobulinemia (WM) in adult patients (Canada, March 2021);
Registered and reimbursed for the treatment of MCL in patients who have received at least one prior therapy (Israel, April 2021);
For the treatment of adult patients with WM who have received at least one prior therapy (China, June 2021)**;
For the treatment of MCL in adult patients who have received at least one prior therapy (Canada, July 2021);
For the treatment of MCL in adult patients who have received at least one prior therapy (Chile, July 2021);
For the treatment of adult patients with MCL who have received at least one previous therapy (Brazil, August 2021);
For the treatment of adult patients with WM (United States, August 2021); and
For the treatment of adult patients with marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen (United States, September 2021)*.
To date, more than 30 marketing authorization applications in multiple indications have been submitted in the United States, China, the European Union, and more than 20 other countries or regions.

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

** This indication was approved under conditional approval. Complete approval for this indication may be contingent upon results from ongoing randomized, controlled confirmatory clinical trials.

IMPORTANT U.S. SAFETY INFORMATION FOR BRUKINSA (ZANUBRUTINIB)

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 3.4% of patients treated with BRUKINSA monotherapy. Hemorrhage events of any grade occurred in 35% of patients treated with BRUKINSA monotherapy.

Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Co-administration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 27% of patients, most commonly pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (26%), thrombocytopenia (11%) and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy. Grade 4 neutropenia occurred in 13% of patients, and Grade 4 thrombocytopenia occurred in 3.6% of patients.

Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted. Treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 8% of patients. Other second primary malignancies included malignant solid tumors (4.0%), melanoma (1.7%) and hematologic malignancies (1.2%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

Cardiac Arrhythmias

Atrial fibrillation and atrial flutter were reported in 3.2% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher events were reported in 1.1% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.

Embryo-Fetal Toxicity

Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week after the last dose.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Adverse reactions

The most common adverse reactions, including laboratory abnormalities, in ≥ 30% of patients who received BRUKINSA (N = 847) included decreased neutrophil count (54%), upper respiratory tract infection (47%), decreased platelet count (41%), hemorrhage (35%), decreased lymphocyte count (31%), rash (31%) and musculoskeletal pain (30%).

Drug Interactions

CYP3A Inhibitors: When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For coadministration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers: Avoid coadministration with moderate or strong CYP3A inducers.

Specific Populations

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

On September 17, 2021 Tachyon Therapeutics, Inc. ("Tachyon" or "the Company"), a research and development biotechnology company, reported an abstract presentation of the Company’s lead product candidate, TACH101, at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) ("ESMO") Annual Meeting. ESMO (Free ESMO Whitepaper) is being held virtually from September 16-21, 2021 (Press release, Tachyon Therapeutics, SEP 17, 2021, View Source [SID1234587904]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

"Triple negative breast cancer represents nearly 20% of all breast cancers and is a highly aggressive subtype that continues to have poor prognosis due to lack of effective treatments," stated Frank Perabo, MD, PhD, CEO of Tachyon Therapeutics. "Large-scale genomic analysis projects show that KDM4 is amplified in about 25% of triple negative breast cancer cases, making KDM4 an attractive epigenetic target for this cancer type. We are anticipating to study TACH101 in the near future in clinical trials."

Highlights from the ESMO (Free ESMO Whitepaper) abstract are summarized below:

Abstract #210P

TACH101 was potent in killing a Triple Negative Breast Cancer (TNBC) cell line (MDA-MB-231) with an IC50 of 0.0035 µM.
TACH101 treatment of MDA-MB-231 TNBC cells caused cell-cycle arrest and induction of apoptosis with an EC50 of 0.132 µM.
In vivo, TACH101 inhibited tumor growth in the COH70 TNBC xenograft model with tumor growth inhibition > 85%.
Gene expression analysis of TACH101-treated tumors show that Protein Phosphatase 1 Regulatory subunit 10 (PPP1R10 or PNUTS), a key regulator of the retinoblastoma protein (Rb) and p53, was a direct target of KDM4 and was significant downregulated after 24 hours of treatment.
The poster presentation of Abstract #210P is available for viewing on the ESMO (Free ESMO Whitepaper) Annual Meeting website at View Source

On September 17, 2021 Daiichi Sankyo Company, Limited reported New first-in-human data from DS-7300, a B7-H3 directed DXd antibody drug conjugate (ADC) being developed in strategic collaboration with Sarah Cannon Research Institute, showed promising early clinical activity in patients with several types of advanced solid tumors (Press release, Daiichi Sankyo, SEP 17, 2021, View Source [SID1234587903]). These results from the dose escalation portion of a phase 1/2 study of DS-7300 were presented during a Proffered Paper session (#513O) at the European Society for Medical Oncology (#ESMO21) 2021 Virtual Congress.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

B7-H3 is frequently overexpressed in a wide range of cancers including lung, prostate, breast, head and neck squamous cell carcinoma, and esophageal squamous cell carcinoma, and its overexpression is associated with poor prognosis.1,2,3 No B7-H3 directed therapies are currently approved for treatment of any cancer.

DS-7300 was tolerated across all dose levels (0.8 mg/kg -16.0 mg/kg) with no dose-limiting toxicities observed in 70 patients enrolled. The most common treatment emergent adverse events (TEAEs) overall in ≥10% of patients were nausea (55.7%), infusion-related reaction (40.0%), decreased appetite (28.6%), vomiting (27.1%), fatigue (21.0%), chills (12.9%), pyrexia (12.9%), dehydration (11.4%) and diarrhea (11.4%). Grade 3 or higher TEAEs regardless of causality occurred in 31.4% of patients (n=22) with the most common being anemia (15.7%) and lymphocyte count decreased (2.8%). One patient receiving the 16.0 mg/kg dose developed interstitial lung disease (ILD) that was associated with death (grade 5) that was adjudicated as treatment related. One case of grade 1 ILD at the 12.0 mg/kg dose that was pending adjudication as of data cut-off of July 21, 2021 has since been adjudicated as treatment related.

Preliminary efficacy results include 15 partial responses (PR), 10 confirmed PRs with 5 additional PRs awaiting confirmation, in patients with a range of solid tumors including metastatic castration-resistant prostate cancer, head and neck squamous cell carcinoma, small cell lung cancer, endometrial cancer, esophageal squamous cell carcinoma and squamous non-small cell lung cancer at doses from 4.8 mg/kg to 16.0 mg/kg. Stable disease has been reported in an additional 32 patients including 24 patients who are still being treated with various doses of DS-7300 as of data cut-off of July 21, 2021. Patients enrolled in the dose escalation study received a median of four prior lines of therapy (range, 1-10).

"These initial safety and efficacy results of DS-7300 are encouraging as we observed that most patients in the study experienced some level of tumor shrinkage," said Melissa Johnson, MD, Director of the Lung Cancer Research Program at Sarah Cannon Research Institute. "Based on these results, we are moving forward with the dose expansion part of the study where we are enrolling patients with metastatic small cell lung cancer, esophageal squamous cell cancer and castration-resistant prostate cancer to further evaluate the potential role of DS-7300 in these cancers."

"These first-in-human results provide preliminary evidence that targeting B7-H3 with DS-7300 may be an effective treatment strategy across several types of cancer where current treatment options are limited," said Gilles Gallant, BPharm, PhD, FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo. "Additionally, these results seen with DS-7300, our fourth DXd ADC in clinical development, may further validate the portability of our DXd ADC technology to other targets to create potential new treatments for patients with cancer."

About B7-H3

B7 homologue 3 (B7-H3) is a transmembrane protein belonging to the B7 family. B7-H3 plays a role in tumor growth as well as in immune response.4,5 B7-H3 is frequently overexpressed in various cancers including lung, prostate, breast, head and neck squamous cell carcinoma, and esophageal squamous cell carcinoma and its overexpression is associated with poor prognosis.1,2,3

About the DS-7300 Study

This first-in-human, open-label phase 1/2 study is evaluating the safety, tolerability and preliminary activity of DS-7300 in adult patients with advanced/unresectable or metastatic solid tumors that are refractory or intolerable to standard treatment or for whom no standard treatment exists.

The first part of the study (dose escalation) is assessing the safety and tolerability of increasing doses of DS-7300 given every three weeks to determine the maximum tolerated dose (MTD) or recommended dose for expansion (RDE). This portion of the trial enrolled 70 patients with advanced/unresectable or metastatic castration-resistant prostate cancer, head and neck squamous cell carcinoma, small cell lung cancer, endometrial cancer, esophageal squamous cell carcinoma, squamous non-small cell lung cancer, breast cancer, melanoma and bladder cancer.

The second part of the study (dose expansion) will be evaluating the safety, tolerability and preliminary activity of DS-7300 at various doses. This portion of the study currently consists of three cohorts of patients with selected advanced/metastatic solid tumors including small cell lung cancer, esophageal squamous cell cancer, and castration-resistant prostate cancer. Additional or alternative indications may be added to expansion cohorts based on preliminary signals of activity.

The study is evaluating safety endpoints including adverse events and efficacy endpoints including objective response rate, duration of response, disease control rate, time to response, progression-free survival and overall survival. Pharmacokinetic endpoints and exploratory biomarker and immunogenicity endpoints also will be assessed.

Patient enrollment into the dose expansion part of the study is underway in Asia and North America. For more information, please visit ClinicalTrials.gov.

About DS-7300

DS-7300 is an investigational B7-H3 directed ADC and is one of six ADCs currently in clinical development in the oncology pipeline of Daiichi Sankyo. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, DS-7300 is comprised of a humanized anti-B7-H3 IgG1 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a tetrapeptide-based cleavable linker. DS-7300 is being developed through a strategic collaboration with Sarah Cannon Research Institute, with study operational oversight and delivery provided through Sarah Cannon’s early phase Oncology CRO, Sarah Cannon Development Innovations.

DS-7300 is an investigational medicine that has not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo in Oncology

The oncology portfolio of Daiichi Sankyo is powered by our team of world-class scientists that push beyond traditional thinking to create transformative medicines for people with cancer. Anchored by our DXd antibody drug conjugate (ADC) technology, our research engines include biologics, medicinal chemistry, modality and other research laboratories in Japan, and Plexxikon, our small molecule structure-guided R&D center in the U.S. We also work alongside leading academic and business collaborators to further advance the understanding of cancer as Daiichi Sankyo builds towards our ambitious goal of becoming a global leader in oncology by 2025.