On January 15, 2025 Zai Lab Limited (NASDAQ: ZLAB; HKEX: 9688) reported positive topline results from the China subpopulation of the global Phase 3 innovaTV 301 study, demonstrating a clinically meaningful improvement in overall survival with TIVDAK treatment for patients with previously treated recurrent or metastatic cervical cancer compared to chemotherapy (Press release, Zai Laboratory, JAN 15, 2025, View Source [SID1234649751]).

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The China subpopulation results were consistent with those in the global population:

TIVDAK demonstrated a 45% reduction in the risk of death compared to chemotherapy (HR: 0.55 [95% CI: 0.27-1.15] in the China subpopulation who had received prior standard systemic therapies, with more than half of this Chinese population having received prior anti-PD(L)1 therapy. Median OS for patients treated with TIVDAK was not reached versus chemotherapy 10.7 months [95% CI: 6.0-not reached] with a median follow-up of 11.5 months.
Secondary endpoints of PFS and confirmed ORR also favored treatment with TIVDAK compared to chemotherapy.
The safety profile of TIVDAK in the China subpopulation was manageable and consistent with the global profile.
"Recurrent or metastatic cervical cancer remains a significant challenge for patients, highlighting a critical unmet need for effective treatments that extend survival after relapse," said Dr. Rafael Amado, M.D., President, Head of Global Research and Development at Zai Lab. "The consistent and positive results in the China subpopulation of the global Phase 3 study reinforce the potential for TIVDAK, the only ADC therapy in this disease setting, to increase options in this therapeutically unmet clinical setting. If approved, we expect TIVDAK to add to ZEJULA and augment our commercial franchise in women’s tumors."

"There are approximately 150,000 new cases of cervical cancer annually in China1, and patients face limited treatment options once their cancer recurs or spreads after initial treatment," said Dr. Lingying Wu, Professor of the Department of Gynecologic Oncology of National Cancer Center / Cancer Hospital Chinese Academy of Medical Sciences. "While the recent adoption of immunotherapy as a first-line treatment in China represents progress, there is a lack of effective options for patients following relapse. The promising results from TIVDAK, which demonstrated superior survival extension in patients whose disease progressed after initial treatments, including prior anti-PD(L)1 treatment, offer hope for addressing this critical unmet need."

In April 2024, the U.S. Food and Drug Administration (FDA) approved the supplemental Biologics License Application (sBLA) granting full approval for TIVDAK (tisotumab vedotin-tftv) for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. The approval was based on results from the global, randomized, Phase 3 innovaTV 301 clinical trial (NCT04697628), which met its primary endpoint, demonstrating overall survival (OS) benefit in adult patients with previously treated recurrent or metastatic cervical cancer treated with TIVDAK compared to chemotherapy.

TIVDAK demonstrated a 30% reduction in the risk of death compared to chemotherapy (hazard ratio [HR]: 0.70 [95% CI: 0.54-0.89], two-sided p=0.0038)2. Median OS for patients treated with TIVDAK was 11.5 months [95% CI: 9.8-14.9] versus chemotherapy 9.5 months [95% CI: 7.9-10.7].
PFS and confirmed ORR were also significantly improved compared to chemotherapy.
The safety profile of TIVDAK was consistent with its known safety profile as presented in the U.S. prescribing information, and no new safety signals were observed.
Based on these encouraging results, Zai Lab intends to submit an NDA for TIVDAK to China’s National Medical Products Administration (NMPA) in the first quarter of 2025. The full China subpopulation data will be presented at a future medical conference in 2025.

About innovaTV 301 Trial Design

The innovaTV 301 trial (NCT04697628) is a global, 1:1 randomized, open-label Phase 3 trial evaluating TIVDAK (tisotumab vedotin) versus investigator’s choice of single agent chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) with recurrent or metastatic cervical cancer who received chemotherapy.

Patients with recurrent or metastatic cervical cancer with squamous cell, adenocarcinoma, or adenosquamous histology, and disease progression during or after treatment with chemotherapy doublet +/- bevacizumab and an anti-PD-(L)1 agent (if eligible) are included. The primary endpoint was overall survival. The main secondary outcomes were progression-free survival and objective response rate.

The study was conducted by Seagen, which was acquired by Pfizer in December 2023, in collaboration with Genmab, European Network of Gynaecological Oncological Trial Groups (ENGOT, study number ENGOT cx-12) and the Gynecologic Oncology Group (GOG) Foundation (study number GOG 3057), as well as other global gynecological oncology cooperative groups.

For more information about the Phase 3 innovaTV 301 clinical trial and other clinical trials with tisotumab vedotin, please visit www.clinicaltrials.gov.

About Cervical Cancer in China

Cervical cancer remains one of the leading causes of cancer death in women in China and globally. An estimated 150,000 new cases of cervical cancer occur annually in China1. Current treatment options are limited for patients with recurrent or metastatic cervical cancer with disease progression on or after systemic therapy. TIVDAK is well positioned to provide a new option for previously treated advanced cervical cancer patients who currently have limited treatment options and poor outcomes.

About TIVDAK (tisotumab vedotin)

TIVDAK (tisotumab vedotin) is an antibody-drug conjugate (ADC) composed of Genmab’s human monoclonal antibody directed to tissue factor (TF) and Pfizer’s ADC technology that utilizes a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody. Nonclinical data suggest that the anticancer activity of tisotumab vedotin is due to the binding of the ADC to TF-expressing cancer cells, followed by internalization of the ADC-TF complex, and release of MMAE via proteolytic cleavage. MMAE disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. In vitro, tisotumab vedotin also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.

TIVDAK received accelerated approval from the FDA in September 2021 and full approval in April 2024 for adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

Please see full prescribing information, including BOXED WARNING for TIVDAK here.

Zai Lab has an exclusive license from Seagen Inc., a company later acquired by Pfizer, to develop and commercialize TIVDAK in Greater China (mainland China, Hong Kong, Macau, and Taiwan, collectively).

On January 15, 2025 OS Therapies, Inc. (NYSE-A: OSTX), a clinical-stage biotechnology company advancing immunotherapies and targeted drug conjugates for cancer treatment, reported positive data from a Phase 2b clinical trial (NCT04974008) of OST-HER2 (OST31-164) – the Company’s HER2-targeted immunotherapy candidate in the rare pediatric-designated indication of prevention of recurrent, fully resected, lung metastatic osteosarcoma (Press release, OS Therapies, JAN 15, 2025, View Source [SID1234649750]). The data demonstrate statistically significant results in the primary endpoint of the study, 12-month event free survival (‘EFS’), where an event is defined as the recurrence of metastatic osteosarcoma, in OST-HER2-treated patients when compared with the leading published historical comparable control group. Further as of the most recent follow up, the data show a strong trend in favor of OST-HER2-treated patients in overall survival (‘OS’, remaining alive) at the 1-year and 2-year interim timepoints of the ongoing 3-year overall survival secondary endpoint. Notably, all patients who achieved the primary 12-month EFS endpoint remain alive.

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"We are extremely pleased with these results of our Phase 2b clinical trial because they show that OST-HER2-treated patients achieved the primary endpoint of 12-month EFS in a statistically significantly higher ratio than comparable historical controls, in addition to increasing the likelihood of 1-year and 2-year survival as compared with comparable historical controls," commented Dr. Robert Petit, Chief Medical & Scientific Officer of OS Therapies. "The strong safety profile shown in this study also supports the use of OST-HER2 in this incredibly difficult-to-treat population that has no currently approved therapies."

"The achievement of the primary endpoint in the OST-HER2 phase 2b is a tremendous success that opens the possibility, for the first time, of meaningful therapy for patients suffering from osteosarcoma with lung metastases after resection. This is a leap forward in the development of OST-HER2 and we are pleased that our regulatory strategy is consistent with the FDA’s recent draft guidance update for accelerated approvals. With these positive data in hand, we are preparing to engage with U.S. FDA on an accelerated pathway for approval in this extremely challenging indication," said Paul Romness, MHP, Chair & CEO of OS Therapies. "We do not expect to have to treat additional patients as part of this process with FDA."

Phase 2b Clinical Trial Data

Enrollment Criteria:

12-39 years old
Recurred, fully resected lung only metastatic (METS) Osteosarcoma
39 evaluable patients at 21 centers, single treatment arm
52 Weeks on Study: Dosed 16 times every 3 weeks for 48 weeks with 4-week follow-up final visit
Primary Endpoint of 12-month EFS:

33% for OST-HER2 vs. 20% for historical control1 (p = 0.0158)
Interim Analysis of Ongoing Secondary Endpoint, OS:

1-year OS: 91% for OST-HER2 vs. 80% for historical control2 (p = 0.0700)
2-year OS: 61% for OST-HER2 vs. 40% for historical control2 (p = 0.0576)
Post-Hoc Analyses

12-months EFS Subgroup Analysis in the OST-HER2 Treatment Group:

Gender (Males vs Females), n = 39:

Females (n=19) = 47%
Males (n= 20) = 20%
(p= 0.0604)
Number of lung resections (1 Prior Resection vs. 2+ Prior Resections), n= 39:

1 Prior Resection (n= 28) = 25%
2+ Prior Resections (n= 11) = 55%
(p = 0.1366)
12-month EFS Responders using a Non-Concurrent Control Group from the only existing US osteosarcoma database with patients qualified for disease-free status following a fully-resected lung-only metastasis of osteosarcoma origin:

OST-HER2, n=39
12-month EFS Responders = 13/39 (33%)
NCCG, n=9
12-month EFS Responders = 1/9 (11%)
(p = 0.1848)
Time to recurrence in patients who did not achieve 12-month EFS:

OST-HER2, n=26 = 5.9 months
NCCG, n=8 = 4.7 months
(p = 0.1454)
About OST-HER2

OST-HER2 is an innovative immunotherapy using a HER2 bioengineered form of the bacteria Listeria monocytogenes (Lm) to trigger a strong immune response against cancer cells expressing HER2. This off-the-shelf immunotherapy treatment is designed to prevent metastasis, delay recurrence, kill primary tumors expressing HER2 alone and potentially in combination with existing approved therapies, and increase overall survival. OST-HER2 has received Rare Pediatric Disease Designation (RPDD) from the FDA and Fast Track and Orphan Drug Designations from the FDA and European Medicines Agency (EMA).

The US FDA granted OST-HER2 rare pediatric disease designation for osteosarcoma in 2021. The US FDA rare pediatric disease PRV program aims to incentivize drug development for rare pediatric diseases. Under this voucher program, a sponsor who receives an approval for a drug or biological product for a rare pediatric disease qualifies for a voucher that can be redeemed to receive priority review for a different product. The sponsor may also transfer or sell the voucher to another sponsor. OS Therapies intends to sell the PRV it would earn upon receiving an approval of OST-HER2 for recurrent, fully resected, lung metastatic osteosarcoma. The most recent publicly disclosed sale price of a PRV was on November 27th, 2024 when PTC Therapeutics announced selling its PRV to Kebilidi for $150M. With emerging scarcity in the PRV market, the Company expects the value of PRVs to increase going forward. The maximum sale price of a PRV was in 2015 when AbbVie bought a priority review voucher from United Therapeutics for $350 million.

The most recent continuing resolution (CR) negotiations in the US House of Representatives failed to reauthorize the PRV program for pediatric cancers such as osteosarcoma. Despite this, as a result of OS Therapies’ having been granted OST-HER2’s rare pediatric disease designation prior to December 20, 2024 in addition to the Company’s aim to receive an approval for OST-HER2 in the rare pediatric disease osteosarcoma in 2025, prior to the September 30, 2026 deadline, OS Therapies remains eligible to receive the PRV upon approval of OST-HER2 in recurrent, resected metastatic osteosarcoma.

The osteosarcoma treatment market was estimated at $1.2 billion in 2022 according to Data Bridge Market Research. Approximately 50% of patients are diagnosed with a lung metastasis at some point following surgical resection and chemotherapy. 3-year survival rates in patients who were not diagnosed with a metastasis are 59%. 3-year survival rates in patients who were diagnosed with pulmonary metastasis were 30%. The Company believes the market opportunity for OST-HER2 in the prevention of lung metastases is over $500 million.

On January 15, 2025 Chromatin Bioscience reported its ongoing collaboration with EsoBiotec, which has successfully advanced its ESO-T01 in vivo CAR-T candidate into clinical trials (Press release, EsoBiotec, JAN 15, 2025, View Source [SID1234649749]). ESO-T01 is the first in vivo B-cell maturation antigen (BCMA) CAR-T candidate to reach the clinical stage and utilises a synthetic promoter designed using Chromatin Bio’s proprietary promoter design platform, chromatinLENS, exclusively for EsoBiotec as part of its innovative approach to immunotherapy.

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EsoBiotec’s ESO-T01, developed using its ENaBL platform, is a T cell targeted lentiviral vector expressing a BCMA-targeted CAR construct for the treatment of multiple myeloma. This construct is regulated by a Treg-specific synthetic promoter developed in collaboration with Chromatin Bioscience. Early studies demonstrated highly effective in vivo transduction, with the BCMA CAR transgene expressed specifically in T cells, leading to the generation of a large population of circulating BCMA CAR-T cells that persisted throughout the study. These results highlight the long-term durability and efficacy of the engineered T cells, marking an important milestone for the therapeutic.

"ESO-T01 is the first in vivo BCMA CAR-T candidate to advance to the clinical stage, showcasing the capabilities of our ENaBL platform technology that reprograms immune cells within the body to combat cancer," stated EsoBiotec CEO Jean-Pierre Latere, Ph.D. "While various treatments exist for multiple myeloma, including ex vivo CAR-T options, many come with severe side effects and are limited by manufacturing capacity, logistical challenges, and high costs. We are excited to collaborate with Chromatin Bioscience to integrate this innovative synthetic promoter, aiming to enhance the safety and efficacy profile of ESO-T01."

Chromatin Bioscience’s chromatinLENS platform allows for the identification of highly specific, cell-type selective gene regulatory elements from the dark genome, offering significant advantages in minimising off-target effects while ensuring robust and durable therapeutic efficacy. These promoters are critical in ensuring the success of advanced therapies like ESO-T01, where targeted expression in T cells is paramount for the safety and efficacy of the treatment.

"EsoBiotec’s progress to the clinic is an exciting development in the field of gene therapy," said Michael Roberts, CEO and Founder of Chromatin Bioscience. "Our synthetic promoters are designed to provide precision and durability in gene expression, and we are pleased that they are playing a role in ensuring the success of ESO-T01. This collaboration represents the power of combining cutting-edge gene therapy with targeted gene expression technologies to offer new treatment options for patients."

On January 15, 2025 Johnson & Johnson (NYSE: JNJ) reported that it has initiated the submission of an original New Drug Application with the U.S. Food and Drug Administration (FDA) for TAR-200 for the treatment of patients with Bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer (HR-NMIBC) with carcinoma in situ (CIS), with or without papillary tumors (Press release, Johnson & Johnson, JAN 15, 2025, View Source [SID1234649748]). This submission is being reviewed by the FDA through the Real-Time Oncology Review (RTOR) program, which allows the FDA to review data before the complete application is formally submitted and helps ensure treatments are available for patients as soon as possible.

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"Upon approval, TAR-200 promises to be a meaningful additional treatment option for certain patients with NMIBC, addressing a critical need for people who have had relatively limited therapeutic alternatives. Many patients face life-altering surgical options such as radical cystectomy, which is complete bladder removal," said Yusri Elsayed, M.D., M.H.Sc., Ph.D., Global Therapeutic Head, Oncology, Johnson & Johnson Innovative Medicine. "By combining our expertise in innovative medicine and medical devices, Johnson & Johnson is uniquely positioned to transform how we treat certain types of bladder cancer through the first and only intravesical drug releasing system for this disease. We look forward to working with the FDA in review of this application."

The submission of this innovative intravesical drug releasing system is supported by data from the Phase 2b SunRISe-1 registration study. Data collected through the second quarter of 2024 and presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2024 Congress as a late-breaking oral presentation showed an 83.5 percent complete response (CR) rate and highly durable CRs without the need for reinduction – at a median follow-up of nine months, 82 percent of responders maintained response. At data cutoff in May 2024, safety and tolerability data presented at ESMO (Free ESMO Whitepaper) demonstrated a low occurrence of Grade 3 or higher treatment-related adverse events (TRAEs) (9 percent); five patients had TRAEs leading to discontinuation (6 percent) and no treatment-related deaths were reported.1

TAR-200 is an investigational intravesical drug releasing system designed to provide sustained local delivery of gemcitabine into the bladder. It is placed into the bladder by a healthcare professional using a co-packaged urinary placement catheter in an outpatient setting in under five minutes and without the need for anesthesia.

In December 2023, the FDA granted Breakthrough Therapy Designation (BTD) to TAR-200 for the treatment of adult patients with BCG-unresponsive HR-NMIBC with CIS who are ineligible for or have elected not to undergo radical cystectomy.

About SunRISe-1, Cohort 2
SunRISe-1 (NCT04640623), Cohort 2, is a randomized, parallel-assignment, open-label Phase 2b clinical study evaluating the safety and efficacy of TAR-200 monotherapy alone for BCG-unresponsive HR-NMIBC carcinoma in situ (CIS) patients who are ineligible for, or elected not to undergo, radical cystectomy. The primary endpoint for Cohort 2 is CR rate at any time point. Secondary endpoints include duration of response (DOR), overall survival (OS), pharmacokinetics, quality of life, safety and tolerability.

About High-Risk Non-Muscle-Invasive Bladder Cancer
High-risk non-muscle-invasive bladder cancer (HR-NMIBC) is a type of non-invasive bladder cancer that is more likely to recur or spread beyond the lining of the bladder, called the urothelium, and progress to invasive bladder cancer compared to low-risk NMIBC.2, 3 HR-NMIBC makes up 15-44 percent of patients with NMIBC and is characterized by a high-grade, large tumor size, presence of multiple tumors, and CIS. Radical cystectomy is currently recommended for NMIBC patients who fail BCG therapy, with over 90 percent cancer-specific survival if performed before muscle-invasive progression.4, 5 Given that NMIBC typically affects older patients, many may be unwilling or unfit to undergo radical cystectomy.6 The high rates of recurrence and progression can pose significant morbidity and distress for these patients.

On January 15, 2025 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, cardiovascular and metabolic, autoimmune, ophthalmology and other major diseases, reported that the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) has granted Breakthrough Therapy Designation (BTD) for IBI343, a potentially best-in-class TOPO1i anti-CLDN18.2 ADC, as monotherapy for the treatment of CLDN18.2-positive advanced pancreatic ductal adenocarcinoma (PDAC) patients who have progressed after at least one line of prior systematic treatment (Press release, Innovent Biologics, JAN 15, 2025, View Source [SID1234649747]).

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The BTD for IBI343 was granted based on data from an ongoing Phase 1 study conducted in China, Australia and the U.S. (NCT05458219), which demonstrated favorable safety and tolerability, as well as promising antitumor activity of IBI343 monotherapy in advanced PDAC patients. Data from the study’s dose-expansion cohort were presented orally at the 2024 ESMO (Free ESMO Whitepaper) Asia Congress:

A total of 43 patients with CLDN18.2-positive advanced PDAC (≥60% tumor cells with membranous staining intensity ≥1+ by IHC) received IBI343 6 mg/kg Q3W monotherapy. All participants had previously received at least one line of prior therapy, and 60.5% had received two or more lines of anticancer treatment.
The confirmed overall objective response rate (ORR) was 23.3%, and progression-free survival (PFS) events occurred in 26 patients, with a median progression-free survival (mPFS) of 5.3 months (4.1-7.4) as of the data cutoff date. (link)
Previously, in May 2024, the CDE has granted IBI343 its first BTD for monotherapy in the treatment of CLDN18.2-positive advanced gastric/gastro-esophageal junction adenocarcinoma (GC) patients who have progressed after at least two lines of prior systematic treatments. In addition, in June 2024, IBI343 was granted Fast Track Designation by the U.S. Food and Drug Administration (FDA) for the treatment of advanced, unresectable or metastatic PDAC that has relapsed and/or is refractory to one prior line of therapy. The first patient in the U.S. Phase 1 study of IBI343 was successfully dosed in December 2024.

Dr. Hui Zhou, Senior Vice President of Innovent, said, "Pancreatic cancer is an aggressive and difficult-to-diagnose malignancy. At present, treatment for advanced pancreatic cancer relies primarily on systemic chemotherapy, with particularly limited options for second-line treatment. This results in poor patient outcomes and underscores an urgent unmet clinical need. As the world’s first CLDN18.2 ADC to receive BTD in this difficult-to-treat cancer, IBI343 monotherapy has shown encouraging efficacy and tolerable safety in late-line treatment of patients with advanced pancreatic cancer. Subject to PoC data readout, we plan to initiate pivotal MRCT studies to further confirm its efficacy and safety in this indication. Additionally, we will also explore the potential of IBI343 in combination therapy for pancreatic cancer and other solid tumors, including gastric cancer."

NMPA Breakthrough Therapy Designation is intended to facilitate and expedite the development and review of investigational drugs for serious diseases or conditions when preliminary clinical evidence indicates substantial improvement over current therapies. BTD qualifies a drug candidate for accelerated review by the CDE and provides the sponsor with timely advice and communication to expedite the approval process, helping to address the unmet clinical needs of patients more swiftly.

About Pancreatic Ductal Adenocarcinoma

Pancreatic cancer is one of the most aggressive malignances of the digestive system, with a 5-year survival rate of about 10%[i]. Despite rising incidence rates in recent years, early detection remains low, seriously endangering human life and health. Current treatment for advanced pancreatic cancer is primarily based on systemic chemotherapy, with first-line treatment options typically including fluorouracil (5-FU) or gemcitabine-based chemotherapy. However, second-line treatment options are limited, offering a chemotherapy response rate of only 6-16%, a median progression free survival of 2 to 5 months, and a median overall survival of approximately 6 to 9 months[ii]. These statistics highlight the urgent need for new therapeutic approaches.

Claudin, a member of the tight junction molecule family, is a key structural and functional component of epithelial tight junctions. Among them, CLDN18.2 is normally confined to the gastric mucosa. The development of malignancy leads to disruption of tight junctions and exposure of CLDN18.2 epitopes on the membrane of tumor cells[iii]. CLDN18.2 is present in 50% to 70% of pancreatic cancer cases, making it a highly targeted biomarker for therapeutic development[iv].

About IBI343 (CLDN18.2 ADC)

IBI343 is an antibody-drug conjugate composed of an anti-CLDN18.2 antibody, and a cytotoxic drug exatecan. Binding of IBI343 to CLDN18.2-expressing tumor cells results in CLDN18.2-dependent internalization of IBI343. Degradation of the cleavable linker will release the drug that causes DNA damage, leading to apoptosis of the tumor cells. The freed drug can also diffuse across the plasma membrane to reach and kill the neighboring tumor cells, resulting in a strong "bystander killing effect" of IBI343. As an innovative TOPO1i ADC, IBI343 has demonstrated tolerable safety and encouraging efficacy signals in Phase 1 clinical studies. The therapeutic potential of IBI343 is currently being explored in tumor types such as gastric and pancreatic cancers, including a Phase 3 trial (NCT06238843) for GC and a multi-regional Phase 1 trial (NCT05458219) for PDAC ongoing.

IBI343 was granted breakthrough therapy designation (BTD) by China’s National Medical Products Administration (NMPA) for two indications, as monotherapy in patients with CLDN18.2–positive GC who progressed after two prior lines of systemic treatment, and in patients with CLDN18.2-positive PDAC who have progressed after at least one line of prior systematic treatment. IBI343 also received Fast Track Designation by the U.S. Food and Drug Administration (FDA) for the treatment of advanced unresectable or metastatic PDAC that has relapsed and/or is refractory to one prior line of therapy.