On January 19, 2024 Johnson & Johnson reported that the U.S. Food and Drug Administration (FDA) approved a supplemental New Drug Application (sNDA) for BALVERSA (erdafitinib) for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) with susceptible fibroblast growth factor receptor 3 (FGFR3) genetic alterations whose disease has progressed on or after at least one line of prior systemic therapy (Press release, Johnson & Johnson, JAN 19, 2024, View Source [SID1234639371]). BALVERSA is not recommended for the treatment of patients who are eligible for and have not received prior PD-1 or PD-L1 inhibitor therapy. This FDA action converts the April 2019 accelerated approval of BALVERSA to a full approval based on the clinical and overall survival benefit observed in the Phase 3 THOR study. BALVERSA is the first oral FGFR kinase inhibitor to be approved, and the first and only targeted treatment for patients with mUC and FGFR alterations.

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Approximately 20 percent of patients with mUC have FGFR3 genetic alterations. After one or more lines of systemic therapy, including a checkpoint inhibitor, these patients generally have a poor prognosis with few available treatment options. This approval is based on results from Cohort 1 of the randomized, controlled, open-label, multicenter Phase 3 THOR study (NCT03390504) confirming the clinical benefit of BALVERSA in extending overall survival (OS) compared to chemotherapy in the second-line setting. Results from the study showed a 36 percent reduction in the risk of death with BALVERSA versus chemotherapy in patients previously treated with a PD-1 or PD-(L)1 inhibitor, with those in the BALVERSA arm living a median of over four months longer (Hazard Ratio (HR) 0.64; [95 percent Confidence Interval (CI), 0.47-0.88]; p=0.0050).1

"Based on results from randomized Phase 3 data, BALVERSA continues to demonstrate the promise of targeted therapy in the treatment of patients with advanced bladder cancer," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Johnson & Johnson Innovative Medicine. "This important milestone reinforces our commitment to advance innovative, precision therapies in oncology and confirm the role of targeted therapy in the treatment of bladder cancer."

Warnings and Precautions in the U.S. Prescribing Information include ocular disorders, hyperphosphatemia and embryo-fetal toxicity. The most common (>20%) adverse reactions, including laboratory abnormalities, were increased phosphate, nail disorders, stomatitis, diarrhea, increased creatinine, increased alkaline phosphate, increased alanine aminotransferase, decreased hemoglobin, decreased sodium, increased aspartate aminotransferase, fatigue, dry mouth, dry skin, decreased phosphate, decreased appetite, dysgeusia, constipation, increased calcium, dry eye, palmar-plantar erythrodysesthesia syndrome, increased potassium, alopecia, and central serous retinopathy. 2

Johnson & Johnson is offering BALVERSA and associated patient services through a single-source specialty pharmacy provider, US Bioservices. This model is part of the Company’s ongoing commitment to provide high-quality products, services, access, and support to healthcare professionals and patients.

The current full Prescribing Information is available at www.BALVERSA.com.

About THOR

THOR (NCT03390504) is a Phase 3 randomized, open-label, multicenter study evaluating the efficacy and safety of BALVERSA. All patients included in the study had metastatic or unresectable UC, with selected FGFR genetic alterations, and showed disease progression during or after one or two prior lines of treatment. The study compared BALVERSA in two cohorts; BALVERSA versus standard of care chemotherapy (investigator’s choice of docetaxel or vinflunine) after at least one line of treatment including an anti-programmed death (ligand) 1 (PD-[L]1) agent (Cohort 1); and BALVERSA compared to pembrolizumab after one prior treatment not containing an anti-PD-(L)1 agent (Cohort 2). The trial consists of screening, a treatment phase (from randomization until disease progression, intolerable toxicity, withdrawal of consent or decision by investigator to discontinue treatment) and a post-treatment follow-up (from end-of-treatment to participant’s death, withdraws consent, or lost to follow-up study completion for the respective cohort, whichever comes first). A long-term extension period is planned for after the clinical cutoff date is achieved for the final analysis of each cohort for patients who continue to benefit from the study intervention. The primary endpoint of the study is OS; progression free survival (PFS), objective response rate (ORR), duration of response (DOR), patient-reported outcomes, safety, and pharmacokinetics (PK) are secondary endpoints.

Results from Cohort 1 were presented in a Late-Breaking Presentation Session (Abstract #LBA4619) at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.1 In June 2023, based on the recommendation of the independent data safety monitoring committee, the THOR study was stopped at the interim analysis for efficacy and all patients randomized to chemotherapy were offered the opportunity to cross over to BALVERSA. Results from Cohort 1 and Cohort 2 of the confirmatory, Phase 3, randomized study were presented at ESMO (Free ESMO Whitepaper) 2023 (Abstract #2359O), and results of Cohort 1 were published in the New England Journal of Medicine in November 2023.

About BALVERSA

BALVERSA (erdafitinib) is a once-daily, oral FGFR kinase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) with susceptible fibroblast growth factor receptor 3 (FGFR3) genetic alterations whose disease progressed on or after at least one line of prior systemic therapy. BALVERSA is not recommended for the treatment of patients who are eligible for and have not received prior PD-1 or PD-(L)1 inhibitor therapy.2 Patients are selected for therapy based on an FDA-approved companion diagnostic for BALVERSA. Information on FDA-approved tests for the detection of FGFR genetic alterations in urothelial cancer is available at: View Source

BALVERSA received Breakthrough Therapy Designation from the U.S. FDA in 2018 and received accelerated approval in 2019 for the treatment of adults with locally advanced or mUC which has susceptible FGFR3 or FGFR2 genetic alterations and who have progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.3

The Company submitted a marketing authorization application to the European Medicines Agency in September 2023 for BALVERSA as a treatment for adult patients with FGFR3-altered, locally advanced unresectable or metastatic urothelial carcinoma that has progressed following therapy with a PD-(L)1 inhibitor.

In 2008, Janssen Pharmaceuticals entered into an exclusive worldwide license and collaboration agreement with Astex Pharmaceuticals to develop and commercialize BALVERSA.

For more information, visit www.BALVERSA.com.

About Urothelial Carcinoma

Urothelial carcinoma, also known as transitional cell carcinoma, starts in the innermost lining of the bladder.4 It is the most common form of bladder cancer, representing more than 90 percent of all bladder cancers.5 Metastatic or unresectable disease is identified in approximately 20 percent of patients presenting with urothelial cancer, and an estimated five to eight percent of all bladder cancers. Approximately one in five patients (20 percent) diagnosed with mUC have an FGFR genetic alteration.6,7 Fibroblast growth factor receptors are a family of receptor tyrosine kinases that can be activated by genetic alterations in a variety of tumor types, and these alterations may lead to increased tumor cell growth and survival. 6,8,9,10,11 Select FGFR genetic alterations can be detected through an FDA-approved companion diagnostic. The five-year survival rate for patients with Stage IV metastatic bladder cancer that has spread to distant parts of the body is currently eight percent.12

BALVERSA IMPORTANT SAFETY INFORMATION

WARNING AND PRECAUTIONS

Ocular Disorders – BALVERSA can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect.

CSR/RPED occurred in 22% of patients treated with BALVERSA, with a median time to first onset of 46 days. In 104 patients with CSR, 40% required dose interruptions and 56% required dose reductions; 2.9% of BALVERSA-treated patients required permanent discontinuation for CSR. Of the 24 patients who restarted BALVERSA after dose interruption with or without dose reduction, 67% had recurrence and/or worsening of CSR after restarting. CSR was ongoing in 41% of the 104 patients at the time of last evaluation.

Dry eye symptoms occurred in 26% of BALVERSA-treated patients. All patients should receive dry eye prophylaxis with ocular demulcents as needed.

Perform monthly ophthalmological examinations during the first 4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms. Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography. Withhold or permanently discontinue BALVERSA based on severity and/or ophthalmology exam findings [see Dosage and Administration (2.3)].

Hyperphosphatemia and Soft Tissue Mineralization – BALVERSA can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcinosis, non-uremic calciphylaxis and vascular calcification. Increases in phosphate levels are a pharmacodynamic effect of BALVERSA [see Pharmacodynamics (12.2)]. Increased phosphate occurred in 73% of BALVERSA-treated patients. The median onset time of increased phosphate was 16 days (range: 8–421) after initiating BALVERSA. Twenty-four percent of patients received phosphate binders during treatment with BALVERSA. Vascular calcification was observed in 0.2% of patients treated with BALVERSA.

Monitor for hyperphosphatemia throughout treatment. In all patients, restrict phosphate intake to 600‑800 mg daily and avoid concomitant use of agents that may increase serum phosphate levels. If serum phosphate is above 7.0 mg/dL, consider adding an oral phosphate binder until serum phosphate level returns to <7.0 mg/dL. Withhold, dose reduce, or permanently discontinue BALVERSA based on duration and severity of hyperphosphatemia [see Dosage and Administration (2.3), Table 2: Dose Modifications for Adverse Reactions].

Embryo-Fetal Toxicity – Based on the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to a pregnant female. In a rat embryo-fetal toxicity study, erdafitinib caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum human recommended dose. Advise pregnant patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

Adverse Reactions

In this pooled safety population of 479 patients who received BALVERSA, the median duration of treatment was 4.8 months (range: 0.1 to 43 months). The most common (>20%) adverse reactions were: increased phosphate, nail disorders, stomatitis, diarrhea, increased creatinine, increased alkaline phosphatase, increased alanine aminotransferase, decreased hemoglobin, decreased sodium, increased aspartate aminotransferase, fatigue, dry mouth, dry skin, decreased phosphate, decreased appetite, dysgeusia, constipation, increased calcium, dry eye, palmar-plantar erythrodysesthesia syndrome, increased potassium, alopecia, and central serous retinopathy.

In Cohort 1 of the BLC3001 study:

Serious adverse reactions occurred in 41% of patients who received BALVERSA. Serious reactions in >2% of patients included urinary tract infection (4.4%), hematuria (3.7%), hyponatremia (2.2%), and acute kidney injury (2.2%). Fatal adverse reactions occurred in 4.4% of patients who received BALVERSA, including sudden death (1.5%), pneumonia (1.5%), renal failure (0.7%), and cardiorespiratory arrest (0.7%).
Permanent discontinuation of BALVERSA due to an adverse reaction occurred in 14% of patients. Adverse reactions which resulted in permanent discontinuation of BALVERSA in >2% of patients included nail disorders (3%) and eye disorders (2.2%).
Dosage interruptions of BALVERSA due to an adverse reaction occurred in 72% of patients. Adverse reactions which required dosage interruption in >4% of patients included nail disorders (22%), stomatitis (19%), eye disorders (16%), palmar-plantar erythrodysesthesia syndrome (15%), diarrhea (10%), hyperphosphatemia (7%), increased aspartate aminotransferase (6%), and increased alanine aminotransferase (5%).
Dose reductions of BALVERSA due to an adverse reaction occurred in 69% of patients. Adverse reactions which required dose reductions in >4% of patients included nail disorders (27%), stomatitis (19%), eye disorders (17%), palmar-plantar erythrodysesthesia syndrome (12%), diarrhea (7%), dry mouth (4.4%), and hyperphosphatemia (4.4%).
Clinically relevant adverse reactions in <15% of patients who received BALVERSA included nausea (15%), pyrexia (15%), epistaxis (13%), vomiting (10%), and arthralgia (10%).
Drug Interactions

Moderate CYP2C9 or Strong CYP3A4 Inhibitors: Consider alternative agents; however, if co-administration is unavoidable monitor closely for adverse reactions. (7.1)
Strong CYP3A4 inducers: Avoid co-administration use with BALVERSA. (7.1)
Moderate CYP3A4 inducers: If co-administration is required at the start of BALVERSA treatment, administer BALVERSA at a dose of 9 mg daily. (7.1)
Serum phosphate level-altering agents: Avoid co-administration use with agents that can alter serum phosphate levels before the initial dose modification period based on serum phosphate levels. (2.3, 7.1)
P-gp substrates: If co-administration is unavoidable separate BALVERSA administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic indices. (7.2)
Use in Specific Populations

Lactation – Because of the potential for serious adverse reactions from erdafitinib in a breastfed child, advise lactating patients not to breastfeed during treatment with BALVERSA and for one month following the last dose.

Please click here to see full BALVERSA Prescribing Information.

On January 19, 2024 Aadi Bioscience, Inc. (NASDAQ: AADI), a biopharmaceutical company focused on developing and commercializing precision therapies for patients with mTOR pathway alterations, reported poster presentations at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal (GI) Cancers Symposium, taking place January 18-20, 2024, in San Francisco, CA (Press release, Aadi Bioscience, JAN 19, 2024, View Source [SID1234639370]).

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Abstract and poster presentation details are below:

Title: "Real-world analysis of patients with advanced gastrointestinal (GI) cancers harboring inactivating TSC1 and TSC2 alterations using the Foundation Medicine genomic database"
Session Title: Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract
Date/Time: January 19, 2024 – 12:30 – 2:00 pm
Abstract: 558
Presenting Author: Dustin Deming, MD

Abstract Highlights:

In a large real-world database of patients with advanced cancer, 1,898 (1.4%) of the 138,671 patients with GI cancers harbored at least one known or likely inactivating alteration in TSC1 or TSC2
TSC1 and/or TSC2 inactivating alterations were present in 6.8% of liver cancers, 1.6% of colorectal cancers, and 0.5% of pancreatic cancers
Across GI malignancies, genes frequently mutated in tumors with wild-type TSC1 and TSC2 were similar to genetic mutations co-occurring in tumors with alterations in TSC1 and/or TSC2
Most TSC1 and/or TSC2 inactivating alterations in liver and pancreatic cancers occurred in the context of low TMB and MSS tumors; whereas increased TMB and MSI signatures were enriched in colorectal cancer with TSC1 and/or TSC2 alterations
Limitations of this exploratory, real-world study include the timing of sampling (at initial diagnosis vs disease progression) and the absence of clinically matched outcomes data. More research is needed to understand the clinical and prognostic implications of these data
The PRECISION 1 study (NCT05103358) is currently enrolling patients with solid tumors harboring TSC1 and/or TSC2 inactivating alterations
Aadi is also presenting Trials-in-Progress (TiP) posters from its PRECISION 1 and NET clinical studies.

Title: " PRECISION 1: A phase 2, multicenter, open-label basket trial of nab-sirolimus for malignant solid tumors harboring pathogenic in activating alterations in TSC1 and TSC2"
Session Title: Trials in Progress Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract
Date/Time: January 19, 2024 – 12:30 – 2:00 pm
Abstract: TPS585
Presenting Author: Dustin Deming, MD

Title: "A phase 2, study of nab-sirolimus in patients with well-differentiated and advanced/metastatic neuroendocrine tumors of the gastrointestinal tract, lunch, or pancreas"
Session Title: Trials in Progress Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract
Date/Time: January 19, 2024 – 12:30 – 2:00 pm
Abstract: TPS601
Presenting Author: Scott Paulson, MD

More information can be found on the ASCO (Free ASCO Whitepaper) GI meeting website.

On January 19, 2024 Jacobio Pharmaceuticals (1167.HK), a clinical-stage oncology company focusing on undruggable targets, reported data of glecirasib in patients with pancreatic cancer and other solid tumors in the oral abstract session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium ("2024 ASCO (Free ASCO Whitepaper) GI") (Press release, Jacobio Pharmaceuticals, JAN 19, 2024, View Source [SID1234639369]).

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As of December 6, 2023, the monotherapy global study of glecirasib enrolled 52 patients with pancreatic cancer and other solid tumors harboring KRAS G12C mutation in China, the United States, Europe, Israel and other regions, including 31 patients with pancreatic cancer, and 21 patients with other solid tumors (8 with biliary tract tumors, 3 with gastric cancer, 3 with small bowel cancer, 2 with appendix cancer, and 5 with other solid tumors).

Among 50 patients with evaluable solid tumors, the confirmed objective response rate (cORR) was 48% (24/50) and the disease control rate (DCR) was 90% (45/50). For second-line and above KRAS G12C mutated pancreatic cancer patients, the cORR was 41.9% (13/31) and the DCR was 93.5% (29/31). The median progression-free survival (mPFS) was 5.6 months, and the median overall survival (mOS) was 10.7 months. In other solid tumor patients, the cORR was 57.9% (11/19), DCR was 84.2% (16/19), the mPFS was 7.0 months, and the mOS has not yet matured. The above safety and efficacy data are better than the published data of similar studies.

Glecirasib has good tolerability and safety characteristics, the majority of treatment-related adverse events (TRAEs)are grades 1-2, and grade 3 or above TRAEs occurred in 25% of patients. No patient has permanently withdrawn from the study due to TRAE.

Professor Lin Shen, director of Peking University Cancer Hospital gastroenterology department, is the principal investigator for this trial. She introduced at the conference, "Pancreatic cancer is a highly malignant tumor, and current patients lack effective standardized treatment methods, with a five-year overall survival rate of only 5%. Every year in China, nearly 1-2% of pancreatic cancer patients carry a KRAS G12C mutation, and the mutation rate in other solid tumors is also around 1%. The clinical data of glecirasib have preliminarily confirmed the efficacy in patients with pancreatic cancer and other solid tumors. Compared with the standard chemotherapy treatment, the ORR of glecirasib is higher, and the safety and tolerance is better. It is expected that glecirasib will accelerate the clinical development in pancreatic cancer and other solid tumors, bringing a better treatment option beyond chemotherapy for patients."

Jacobio continues to explore the application of glecirasib in pancreatic cancer. Glecirasib’s registrational pivotal study for pancreatic cancer was approved by CDE in July 2023, which became the first global pancreatic cancer KRAS G12C registrational clinical study. The study results will be used to submit NDA (New Drug Application) for pancreatic cancer.

Based on the clinical efficacy and safety data from ongoing clinical trials, glecirasib was granted breakthrough therapy designation (BTD) by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) for the pancreatic cancer patients with a KRAS G12C mutation who have progressed after frontline standard care treatment. Pancreatic cancer is a malignant tumor and there is a lack of effective treatment currently. The five-year overall survival rate is only 5%-10%. The BTD will expedite the clinical development of glecirasib and accelerate its early access to the patients.

For more information, please visit the official website of the ASCO (Free ASCO Whitepaper) GI: View Source

Conference Call Information

Jacobio will host a live conference call on Jan. 23, 2024, at 9:30-10:30 (UTC+8). Participants must register in advance of the conference call.
Registration Link: View Source

About Glecirasib
Glecirasib is a KRAS G12C inhibitor developed by Jacobio. A number of Phase I/II clinical trials of glecirasib are currently ongoing in China, the United States and Europe for patients with advanced solid tumors harboring KRAS G12C mutation. This includes a pivotal clinical trial in NSCLC in China (patients enrollment has been completed); a monotherapy study for STK11 co-mutated NSCLC in the front-line setting, combination therapy trials with SHP2 inhibitor JAB-3312 in NSCLC and with Cetuximab in colorectal cancer, and a registrational pivotal clinical trial in pancreatic cancer.

On January 19, 2024 Astrazeneca reported that Positive results from the EMERALD-1 Phase III trial showed Imfinzi (durvalumab) in combination with TACE and bevacizumab demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of progression-free survival (PFS) compared to TACE alone in patients with hepatocellular carcinoma (HCC) eligible for embolisation (Press release, AstraZeneca, JAN 19, 2024, View Source [SID1234639367]).

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These results will be presented today at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO GI) in San Francisco, California (#LBA432).

Approximately 20-30% of patients with HCC, the most common type of liver cancer, are eligible for embolisation, a procedure that blocks the blood supply to the tumour and can also deliver chemotherapy or radiation therapy directly to the liver.1-8 Despite being the standard of care in this setting, most patients who receive embolisation experience disease progression or recurrence within eight months.9-11

In EMERALD-1, treatment with Imfinzi plus TACE and bevacizumab reduced the risk of disease progression or death by 23% compared to TACE alone (based on a hazard ratio [HR] of 0.77; 95% confidence interval [CI] 0.61-0.98; p=0.032). Median PFS was 15 months in patients treated with the Imfinzi combination versus 8.2 months with TACE. The PFS benefit observed was generally consistent across key prespecified subgroups. The secondary endpoint of time to progression (TTP) further supports the clinical benefit of Imfinzi plus TACE and bevacizumab in this setting, with a median TTP of 22 months versus 10 months for TACE (HR 0.63; 95% CI 0.48-0.82).

The trial will continue as planned to assess the key secondary endpoint of overall survival (OS).

Bruno Sangro, MD, PhD, Director of the Liver Unit and Professor of Medicine at Clínica Universidad de Navarra, Pamplona, Spain and a lead investigator in the EMERALD-1 trial, said: "In this earlier liver cancer setting, embolisation alone has been the standard of care for more than 20 years, and rates of disease progression have remained high. Adding durvalumab and bevacizumab to TACE reduced the risk of disease progression or death by twenty-three per cent for patients with liver cancer eligible for embolisation, showing for the first time that combining a systemic treatment with TACE meaningfully improves this clinically relevant outcome in earlier-stage disease."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "With Imfinzi-based treatment, patients with liver cancer eligible for embolisation lived nearly seven additional months before their disease progressed. We are discussing these positive EMERALD-1 data with global regulatory authorities while awaiting the final overall survival results from the trial."

Summary of results: EMERALD-1i

Imfinzi plus TACE and bevacizumab

(n=204)

Placebo plus TACE

(n=205)

Median PFS (months; 95% CI)ii, iii

15.0 (11.1-18.9)

8.2 (6.9-11.1)

PFS HR (95% CI)ii, iv

0.77 (0.61-0.98)

p-valuev

0.032

PFS rate at 12 months (%)iii

55.5

39.8

PFS rate at 18 months (%)iii

43.1

28.3

Median TTP (months; 95% CI)iii, v

22.0 (16.6-24.9)

10.0 (7.1-13.6)

TTP HR (95% CI)iv, v

0.63 (0.48-0.82)

Subjects with measurable disease

Imfinzi plus TACE and bevacizumab

(n=202)

Placebo plus TACE

(n=203)

Objective Response Rate (ORR) (%)iii

43.6

29.6

i The data cut-off date was 11 Sep 2023.

ii PFS, TTP and ORR by Blinded Independent Central Review (BICR) per RECIST v1.1

iii Calculated using Kaplan-Meier method

iv Calculated from stratified Cox proportional hazards method

v The threshold of significance for this analysis was 0.0435 based on the alpha spend at the PFS interim analysis (2.27%) and the actual number of events at PFS final analysis.

The safety profile for Imfinzi plus TACE and bevacizumab was generally manageable and consistent with the known profile of each medicine. The number of TACE procedures was consistent across arms. No new safety signals were observed. Grade 3 and 4 adverse events due to any cause occurred in 45.5% of patients treated with Imfinzi plus TACE and bevacizumab and 23% of patients treated with TACE alone.

Notes

Liver cancer
Liver cancer, of which HCC is the most common type, is the third-leading cause of cancer death, with an estimated 900,000 people worldwide diagnosed each year and a high prevalence in certain regions of Asia.12-14 An estimated 80-90% of all patients with HCC also have cirrhosis.15 Chronic liver diseases such as cirrhosis are associated with inflammation that over time can lead to the development of HCC.15 Immunotherapy is a proven treatment modality in HCC with approved options available for patients in later-line settings.16

EMERALD-1
EMERALD-1 is a randomised, double-blind, placebo-controlled, multicentre, global Phase III trial of Imfinzi plus TACE concurrently, followed by Imfinzi with or without bevacizumab until progression versus TACE alone in a total of 616 patients with unresectable HCC eligible for embolisation.

The trial was conducted in 157 centres across 18 countries, including in North America, Australia, Europe, South America and Asia. The primary endpoint was PFS for Imfinzi plus TACE and bevacizumab versus TACE alone, and secondary endpoints include PFS for Imfinzi plus TACE, OS, patient-reported outcomes and ORR.

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.

Imfinzi is approved in combination with chemotherapy (gemcitabine plus cisplatin) in locally advanced or metastatic biliary tract cancer (BTC) and in combination with Imjudo (tremelimumab) in unresectable HCC in the US, EU, Japan, China and many other countries based on the TOPAZ-1 and HIMALAYA Phase III trials, respectively. Following HIMALAYA in the advanced setting, EMERALD-1 is AstraZeneca’s second positive Phase III trial in HCC.

In non-small cell lung cancer (NSCLC), Imfinzi is approved in combination with a short course of Imjudo and chemotherapy for the treatment of metastatic NSCLC in the US, EU and Japan based on the POSEIDON Phase III trial. Imfinzi is also the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III NSCLC in patients whose disease has not progressed after chemoradiation therapy based on the PACIFIC Phase III trial, the results of which have been confirmed in the real-world setting in the PACIFIC-R study. In 2023, AstraZeneca announced positive results from the AEGEAN Phase III trial evaluating Imfinzi in combination with neoadjuvant chemotherapy before surgery and as adjuvant monotherapy after surgery in resectable NSCLC.

Imfinzi is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage small cell lung cancer (SCLC) based on the CASPIAN Phase III trial. Imfinzi is approved in previously treated patients with advanced bladder cancer in a small number of countries.

Since the first approval in May 2017, more than 200,000 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, several GI cancers, breast cancer and other solid tumours. In 2023, AstraZeneca announced positive results for several Phase III trials evaluating Imfinzi in various combinations, including in ovarian (DUO-O) and endometrial (DUO-E) cancers with Lynparza (olaparib).

In GI cancers specifically, AstraZeneca has an extensive clinical development programme further assessing Imfinzi across multiple settings. In addition to EMERALD-1, Imfinzi is also being investigated in combination with bevacizumab in adjuvant HCC (EMERALD-2), in combination with Imjudo, lenvatinib and TACE in embolisation-eligible HCC (EMERALD-3), in resectable gastric and gastroesophageal junction cancers (MATTERHORN) and in locally advanced oesophageal cancer (KUNLUN). In June 2023, Imfinzi added to standard-of-care neoadjuvant chemotherapy met a key secondary endpoint of pathologic complete response in the MATTERHORN Phase III trial.

On January 19, 2024 Novartis reported data from the Phase III NETTER-2 trial showing that Lutathera (INN: lutetium (177Lu) oxodotreotide / USAN: lutetium Lu 177 dotatate) plus long-acting release (LAR) octreotide reduced the risk of disease progression or death by 72% as first-line therapy in patients with somatostatin receptor-positive (SSTR+) well-differentiated grade 2/3 advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) versus high-dose octreotide LAR alone (Press release, Novartis, JAN 19, 2024, View Source [SID1234639366]). Data were presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal (GI) Cancers Symposium.

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"These positive results for Lutathera are practice-changing and offer new first-line treatment data for patients who have a significant unmet need. This study confirms the clinical benefit of first-line radioligand therapy for newly diagnosed patients living with these types of advanced GEP-NETs," said Dr. Simron Singh, Associate Professor of Medicine at the University of Toronto and cofounder of the Susan Leslie Clinic for Neuroendocrine Tumours at the Odette Cancer Centre, Sunnybrook Health Sciences Centre, Ontario, Canada. "These findings should instill confidence among physicians in using Lutathera as a first-line treatment for patients with this life-threatening type of cancer."

Efficacy endpoint1 Lutathera plus octreotide LAR vs. high-dose octreotide LAR
Progression-free survival HR 0.28 (95% CI: 0.18, 0.42; p<0.0001)
Median PFS (months) 22.8 month (95% CI: 19.4 -not estimable) vs. 8.5 months (95% CI: 7.7-13.8)
Objective response rate (ORR)* 43% (95% CI: 35.0-51.3) vs. 9.3% (95% CI: 3.8-18.3), p<0.0001
*Assessed via RECIST 1.1
"This is the first positive Phase III trial of a radioligand therapy in the first-line setting, and the overall efficacy and safety results are amongst the most clinically relevant observed to date in this kind of advanced cancer, addressing a significant unmet need for patients with newly diagnosed advanced GEP-NETs," said Jeff Legos, Global Head of Oncology Development at Novartis. "The positive results are a significant advancement and further reaffirm our strategy to research and develop radioligand therapies in earlier lines of treatment or stages of disease to improve outcomes for patients."

No new or unexpected safety findings were observed in the study and data are consistent with the already well-established safety profile of Lutathera1. Most patients (88%) in the Lutathera arm received all four cycles of Lutathera treatment. The most common all-grade AEs (≥20%) for the Lutathera arm vs. control arm were nausea (27.2% vs 17.8%), diarrhea (25.9% vs 34.2%) and abdominal pain (17.7% vs 27.4%), and the most common grade ≥3 AE (>5%) was lymphocyte count decreased (5.4% vs 0%).

NETs are a type of cancer that originate in neuroendocrine cells throughout the body and are commonly considered slow-growing malignancies. However, some NETs are associated with rapid progression and poor prognosis and in many cases, diagnosis is delayed until patients have advanced disease2-4. Even though NETs are a rare (orphan) disease, their incidence has increased over the past several decades2-5 and there is a need for continued research into treatment options for newly diagnosed patients.

The NETTER-2 trial is ongoing for further evaluation of secondary endpoints including overall survival and long-term safety.

About NETTER-2
NETTER-2 (NCT03972488) is an open-label, multi-center, randomized, comparator-controlled Phase III trial assessing whether Lutathera plus octreotide LAR when taken as a first-line treatment can prolong PFS in patients with high-proliferation rate tumors (G2 and G3), compared to treatment with high-dose (60 mg) long-acting octreotide6. Eligible patients were diagnosed with SSTR-positive advanced GEP-NETs within 6 months before enrollment6.

About Lutathera
Lutathera (INN: lutetium (177Lu) oxodotreotide / USAN: lutetium Lu 177 dotatate) is approved in the US for the treatment of adult patients with SSTR-positive GEP-NETs, including those in the foregut, midgut and hindgut, an indication which includes the NETTER-2 population. Lutathera is also approved in Europe for unresectable or metastatic, progressive, well-differentiated (G1 and G2), SSTR-positive GEP-NETs in adults7,8, and in Japan for SSTR-positive NETs.