On January 24, 2025 Exelixis, Inc. (Nasdaq: EXEL) reported results from a subgroup analysis of the phase 3 CABINET pivotal study of patients with extra-pancreatic neuroendocrine tumors (epNET) arising in the gastrointestinal (GI) tract (Press release, Exelixis, JAN 24, 2025, View Source [SID1234649868]). The analysis showed cabozantinib was associated with an improvement in progression-free survival (PFS) compared with placebo in patients with advanced GI neuroendocrine tumors (NET), which was a subgroup of the epNET cohort. These results are being presented today during Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract, at 11:30 a.m. PT on January 24 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2025 Gastrointestinal Cancers Symposium (ASCO GI 2025).

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"Treating neuroendocrine tumors after disease progression can be challenging, including for those with tumors in the gastrointestinal tract, as treatment options are limited," said Jonathan Strosberg, M.D., President Emeritus, North American Neuroendocrine Tumor Society and Chair, GI Research Program, Moffitt Cancer Center and Research Institute. "This subgroup analysis from the CABINET study showed that cabozantinib improved progression-free survival for patients with tumors arising in the GI tract and provides a more detailed picture of how patients with the most common form of this cancer may benefit from this treatment. As a physician, I’m encouraged by these findings, as they suggest cabozantinib has potential to become a standard of care for patients greatly in need of new options."

This subgroup analysis included 116 of the 203 patients in the epNET cohort. The most common primary tumor locations were ileum/cecum (54%), small intestine with location not specified (20%), non-cecum colon or rectum (11%), stomach (4%), duodenum (3%), jejunum (3%) and non-specified midgut site (3%).

Cabozantinib was associated with improved PFS by blinded independent central review compared with placebo for patients with GI NET (hazard ratio: 0.50; 95% confidence interval: 0.28-0.88; one-sided stratified log-rank P=0.007). Median PFS was 8.5 months with cabozantinib compared with 5.6 months with placebo. Cabozantinib demonstrated potential benefit across clinical factors, including grade, functional status, concurrent somatostatin agent use, and prior therapy with Lu-177 dotatate or everolimus. One patient achieved a partial response with cabozantinib versus none with placebo, and 48 versus 30 patients, respectively, achieved stable disease.

"These new data add to the robust results from the CABINET trial that demonstrate the benefits of cabozantinib across a wide range of patients with neuroendocrine tumors and further underscore the potential of cabozantinib to become a much-needed new option for those with GI NET, which accounts for the majority of real-world patients with this tumor type," said Amy Peterson, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. "We look forward to continuing to work with the U.S. FDA as they review our regulatory application for cabozantinib for the treatment of patients with previously treated advanced neuroendocrine tumors."

The safety profile of cabozantinib observed in patients with GI NET was consistent with its known safety profile; no new safety signals were identified. The most frequent grade 3/4 adverse events included hypertension (19% of patients receiving cabozantinib and 4% receiving placebo), diarrhea (13% and 4%, respectively) and fatigue (10% and 4%). Three grade 5 events occurred in the cabozantinib arm possibly related to cabozantinib: one due to cardiac arrest and two not specified.

As announced in August 2023, the Alliance for Clinical Trials in Oncology independent Data and Safety Monitoring Board unanimously recommended that the CABINET trial be stopped early and unblinded due to the substantial improvement in PFS observed at an interim analysis. Final PFS results were presented at the 2024 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress and published concurrently in the New England Journal of Medicine. In August 2024, Exelixis announced that the U.S. Food and Drug Administration (FDA) had accepted the supplemental New Drug Application (sNDA) for cabozantinib for the treatment of previously treated, advanced NET and assigned a Prescription Drug User Fee Act target action date of April 3, 2025.

About CABINET (Alliance A021602)

CABINET (Randomized, Double-Blinded Phase III Study of CABozantinib versus Placebo In Patients with Advanced NEuroendocrine Tumors After Progression on Prior Therapy) is sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and is being led and conducted by the NCI-funded Alliance for Clinical Trials in Oncology with participation from the NCI-funded National Clinical Trials Network as part of Exelixis’ collaboration through a Cooperative Research and Development Agreement with the NCI’s Cancer Therapy Evaluation Program.

CABINET is a multicenter, randomized, double-blinded, placebo-controlled phase 3 pivotal trial that had enrolled a total of 298 patients in the U.S at the time of the final analysis. Patients were randomized 2:1 to cabozantinib (60 mg) or placebo in two separately powered cohorts (pancreatic NET, n=95; epNET, n=203). The epNET cohort included patients with the following primary tumor sites: GI tract, lung, unknown primary sites, and other organs. Each cohort was randomized separately and had its own statistical analysis plan. Patients must have had measurable disease per RECIST 1.1 criteria and must have experienced disease progression or intolerance after at least one U.S. FDA-approved line of prior systemic therapy other than somatostatin analogs. The primary endpoint in each cohort was PFS per RECIST 1.1 by blinded independent central review. Secondary endpoints included overall survival, objective response rate and safety. More information about this trial is available at ClinicalTrials.gov.

About NET

NET are cancers that begin in the specialized cells of the body’s neuroendocrine system.1 These cells have traits of both hormone-producing endocrine cells and nerve cells.1 In 2024, the estimated prevalence of NET in the U.S. was more than 380,000 people.2 It is estimated that 161,000 to 192,000 people are living with unresectable, locally advanced or metastatic NET.2 The number of people diagnosed with NET has been increasing in recent decades.3 Functional NET release peptide hormones that can cause debilitating symptoms, like diarrhea, hypertension and flushing, which may require focused treatment, while symptoms of non-functional NET are related primarily to tumor growth.4,5 Most NET take years to develop and grow slowly, but eventually all patients with advanced or metastatic NET will develop refractory and progressing disease.6,7

NET can develop in any part of the body, but most commonly start in the GI tract or in the lungs, where they have historically been referred to as carcinoid tumors and are more recently called epNET.1 The five-year survival rates for advanced GI and lung NET tumors are 68% and 55%, respectively.8,9 NET can also start in the pancreas, where they tend to be more aggressive, with a five-year survival rate of only 23% for advanced disease.1,10 For advanced NET patients, treatment options include somatostatin analogs, chemotherapy, molecular targeted therapy and peptide-receptor radionuclide therapy.11

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved as monotherapy for the treatment of patients with advanced renal cell carcinoma (RCC) and in combination with nivolumab for patients as a first-line treatment for patients with advanced RCC; for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib, and; for adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in over 65 countries outside the U.S. and Japan, including the European Union. In 2016, Exelixis granted Ipsen Pharma SAS exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the U.S.

CABOMETYX is not indicated as a treatment for NET.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.

Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.

Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.

Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.

In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

On January 24, 2025 Elevar Therapeutics, Inc., a portfolio company of HLB Co., Ltd., reported the results from a post-hoc analysis of the international CARES-310 study evaluating camrelizumab plus rivoceranib vs. sorafenib as a first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC) of viral and non-viral etiology (Press release, Elevar Therapeutics, JAN 24, 2025, View Source [SID1234649867]). The post-hoc analysis will be presented in a poster at the 2025 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s annual Gastrointestinal Cancers Symposium (ASCO GI) on January 24.

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"This post-hoc analysis of uHCC patients treated with camrelizumab and rivoceranib demonstrated consistent survival benefits across subgroups with hepatitis B, hepatitis C and non-viral etiologies. The exploratory analysis revealed clinically meaningful improvements in both overall survival and progression-free survival, agnostic of the underlying etiology. Importantly, the safety profile of the combination therapy remained manageable and comparable across all subgroups," commented Chris Galloway, M.D., senior vice president of clinical development and medical affairs at Elevar.

Results: Median overall survival (mOS) was longer with camrelizumab plus rivoceranib compared with sorafenib in patients with non-viral (HR 0.68 [95% CI 0.39, 1.19]), HCV (HR 0.37 [95% CI 0.162, 0.84]), and HBV etiologies (HR 0.70 [95% CI 0.55, 0.89]). Similarly, median progression free survival (mPFS) was longer with camrelizumab plus rivoceranib compared with sorafenib in patients with non-viral (HR 0.55 [95% CI 0.34, 0.91]), HCV (HR 0.50 [95% CI 0.23, 1.06]), and HBV etiologies (HR 0.57 [95% CI 0.45, 0.72])[i].

The analysis concluded camrelizumab plus rivoceranib in CARES-310 suggested clinically meaningful mOS benefit in non-viral and viral HCC vs sorafenib and provides assurance of clinical benefit for first line treatment to patients with uHCC independent of etiology.[ii]

2025 ASCO (Free ASCO Whitepaper) GI Poster Session Information

Poster Session B, Cancers of the Pancreas, Small Bowel and Hepatobiliary Tract: Clinical outcomes of camrelizumab + rivoceranib vs sorafenib (CARES-310) as first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC) of non-viral and viral etiology.

Abstract: 578 Poster Bd#: C4 Presenter: Rachna T. Shroff, MD, FASCO

About CARES-310

The CARES-310 study, an international, randomized, open-label, Phase 3 trial, with 543 patients with uHCC who had not previously received systemic treatment was the first to demonstrate significant progression-free survival (PFS) and overall survival (OS) benefits with immunotherapy plus an anti-angiogenic tyrosine kinase inhibitor (TKI) over standard TKI as first-line treatment for uHCC. In the primary analysis of PFS (data cut-off [DCO], May 10, 2021) and interim analysis of OS (DCO, Feb. 8, 2022), significant improvements were observed with camrelizumab (C; anti-PD-1 antibody) + rivoceranib (R; VEGFR2-TKI) vs. sorafenib (S).

In the final analysis (FA) of the CARES-310 study, after an additional follow-up of ~16 months, median OS was significantly prolonged with C+R vs. S (23.8 mo [95% CI 20.6-27.2] vs. 15.2 mo [95% CI 13.2-18.5]; hazard ratio (HR) 0.64 [95% CI 0.52-0.79]; 1-sided p <0.0001). OS rate with C+R vs. S was 49.0% vs. 32.6% at 24 mo, and 37.7% vs. 24.8% at 36 mo. OS benefits with C+R was generally consistent across subgroups, regardless of geographical region, race, and etiology. Benefits in PFS, objective response rate (ORR) and duration of response (DoR) with C+R vs. S were also sustained after prolonged follow-up. Safety data aligned with the interim OS analysis, with no new signals noted. In the FA, C+R continued to show clinically meaningful survival improvement compared with S, with manageable safety. The extended follow-up further confirmed the favorable benefit-to-risk profile of C+R, supporting it as a new first-line treatment option for uHCC.

About Hepatocellular Carcinoma

Worldwide each year more than 800,000 people are diagnosed with liver cancer and the disease is the cause of more than 830,000 deaths. Hepatocellular Carcinoma (HCC) is the most common type of liver cancer and most frequently develops in people with chronic underlying liver inflammation which may be from viral and non-viral causes. HCC typically has a poor prognosis with limited treatment options and continues to be a diagnosis with an ongoing urgent medical need.

About Rivoceranib

Rivoceranib, a small-molecule tyrosine kinase inhibitor (TKI), is a highly selective inhibitor of vascular endothelial growth factor receptors (VEGFRs), a primary pathway for tumor angiogenesis. VEGFR inhibition is a clinically validated target to limit tumor growth and disease progression. Rivoceranib is currently being studied as a monotherapy and in combination with chemotherapy and immunotherapy in various solid tumor indications. Several clinical studies were completed in patients with uHCC (in combination with camrelizumab), gastric cancer (as a monotherapy and in combination with paclitaxel), adenoid cystic carcinoma (as a monotherapy) and colorectal cancer (in combination with Lonsurf). Rivoceranib, under the name apatinib (Aitan), was the first TKI approved in gastric cancer in China (October 2014). It was also approved in China in combination with camrelizumab as a first-line treatment for uHCC (January 2023). The drug has been studied in more than 6,000 patients worldwide and was well tolerated in clinical trials with a comparable safety profile to other TKIs and VEGF inhibitors. Orphan drug designations have been granted for gastric cancer (U.S., EU and South Korea), adenoid cystic carcinoma (U.S.) and uHCC (U.S. and EU). Elevar Therapeutics, Inc. holds the global rights (excluding China) to rivoceranib and has partnered for its development and marketing with HLB-LS in South Korea. Jiangsu Hengrui Pharmaceuticals Company Ltd., (Hengrui Pharma), is the Chinese -territory license-holder of rivoceranib.

About Camrelizumab

Camrelizumab (SHR-1210) is a humanized monoclonal antibody that binds to the programmed death-1 (PD-1) receptor. Blockade of the PD-1/PD-L1 signaling pathway is a therapeutic strategy showing success in a wide variety of solid and hematological cancers. Camrelizumab is developed by Hengrui Pharma and has been studied in more than 5,000 patients. Currently, 50 clinical trials are underway in a broad range of tumors (including liver cancer, lung cancer, gastric cancer, and breast cancer, etc.) and treatment settings. Camrelizumab, under the brand name AiRuiKa, is currently approved for eight indications in China, including monotherapy for the treatment of HCC (second-line), in combination with rivoceranib as a treatment for uHCC (first-line), relapsed/refractory classic Hodgkin’s lymphoma (third-line), esophageal squamous cell carcinoma (second-line) and nasopharyngeal carcinoma (third-line or further) and in combination with chemotherapy for the treatment of non-small cell lung cancer (non-squamous and squamous), esophageal squamous cell carcinoma and nasopharyngeal carcinoma in the first-line setting. The U.S. Food and Drug Administration granted Orphan Drug Designation to camrelizumab for advanced HCC in April 2021 and by the European Medicines Agency in August 2024.

In October 2023, Elevar licensed camrelizumab, an anti-PD-1 antibody, for commercialization from Jiangsu Hengrui Pharmaceuticals Co., Ltd. (Hengrui Pharma) worldwide excluding Greater China and Korea.

On January 24, 2025 Eisai (Headquarters: Tokyo, CEO: Haruo Naito) and Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside of the United States and Canada) reported results from the Phase 3 LEAP-015 trial evaluating LENVIMA (lenvatinib), the orally available multiple receptor tyrosine kinase inhibitor (TKI) discovered by Eisai, plus KEYTRUDA (pembrolizumab), the anti-PD-1 therapy from Merck & Co., Inc., Rahway, NJ, USA, in combination with chemotherapy (LENVIMA plus KEYTRUDA-based regimen), for the first-line treatment of patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal adenocarcinoma (Press release, Eisai, JAN 24, 2025, View Source [SID1234649865]).

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At an interim analysis, the LENVIMA plus KEYTRUDA-based regimen demonstrated a statistically significant improvement in progression-free survival (PFS), one of the study’s dual primary endpoints, and objective response rate (ORR), a key secondary endpoint, compared to standard of care chemotherapy. The study continued, and at the final analysis, it did not meet its other primary endpoint of overall survival (OS). The safety profile of the LENVIMA plus KEYTRUDA-based regimen was consistent with that observed in previously reported studies evaluating the combination. A full evaluation of the data from this study is ongoing, and Eisai and Merck & Co., Inc., Rahway, NJ, USA will present these results at an upcoming medical meeting.

"Locally advanced unresectable or metastatic gastroesophageal adenocarcinoma remains a challenging disease to treat and a leading cause of cancer death worldwide," said Dr. Gregory Lubiniecki, Vice President, Global Clinical Development, MSD Research Laboratories. "These study results add to our understanding of this combination and will inform our future research as we strive to improve outcomes for more patients with cancer."

"Gastric and gastroesophageal cancers continue to present challenges due to their heterogeneity and generally poor prognoses," said Dr. Corina Dutcus, Senior Vice President, Oncology Global Clinical Development Lead at Eisai Inc. "While the LEAP-015 trial did not show a statistically significant increase in overall survival, we were pleased to observe an improvement in progression-free survival and objective response rate for patients treated with LENVIMA plus KEYTRUDA in combination with chemotherapy. These results contribute to the scientific community’s collective understanding of these complex diseases and add to the body of knowledge in oncology research. We are deeply grateful to the patients, caregivers and investigators who participated in this study."

LENVIMA plus KEYTRUDA is approved in the U.S., the EU, Japan and other countries for the treatment of advanced renal cell carcinoma (RCC) and certain types of advanced endometrial carcinoma. Lenvatinib is marketed as KISPLYX for advanced RCC in the EU. Eisai and Merck & Co., Inc., Rahway, NJ, USA are studying the LENVIMA plus KEYTRUDA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in hepatocellular carcinoma and esophageal cancer across multiple clinical trials.

Results from the LEAP-015 trial do not affect the current approved indications for KEYTRUDA plus LENVIMA or other ongoing trials from the LEAP clinical program.

About Leap-015

LEAP-015 is a randomized, open-label, Phase 3 trial (ClinicalTrials.gov, NCT04662710) evaluating LENVIMA plus KEYTRUDA in combination with chemotherapy versus chemotherapy alone for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastroesophageal adenocarcinoma. There are two parts of the study: a safety run-in (Part 1) and the main study (Part 2). In Part 2, the primary endpoints are OS and PFS as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) in patients whose tumors express PD-L1 (Combined Positive Score [CPS] ≥1) and in all patients. Secondary endpoints are ORR and duration of response (DOR) as assessed by BICR per RECIST v1.1 in both patients whose tumors express PD-L1 (CPS ≥1) as well as in all patients, and safety. In Part 2, up to 880 patients were randomized 1:1 to receive:

• LENVIMA plus KEYTRUDA plus chemotherapy:
o Induction Phase: approximately 12 weeks
 Oral LENVIMA 8 mg every day (QD) plus KEYTRUDA 400 mg intravenously (IV) every six weeks (Q6W) x 2 cycles plus chemotherapy (CAPOX or mFOLFOX6)
• CAPOX: oral capecitabine 1000 mg/m2 twice daily (BID) for 14 days plus oxaliplatin 130 mg/m2 IV, every 3 weeks (Q3W) x 4 cycles or
• mFOLFOX6: bolus IV 5-fluorouracil (5-FU) 400 mg/m2, plus 5-FU 2400 mg/m2 continuous IV plus leucovorin 400 mg/m2 IV or levoleucovorin 200 mg/m2 IV plus oxaliplatin 85 mg/m2 IV, every 2 weeks (Q2W) x 6 cycles
o Consolidation Phase:  Oral LENVIMA 20 mg QD, plus KEYTRUDA 400 mg IV Q6W, for less than or equal to 16 doses ; or
• Chemotherapy (either CAPOX regimen or mFOLFOX6 regimen, dosed as above; maximum cycles per local standards).

About Gastric Cancer

Gastric (stomach) cancer tends to develop slowly over many years and rarely causes early symptoms, resulting in most cases going undetected until an advanced stage.1,2 More than 70% of patients with gastric cancer develop advanced-stage disease.3 Most gastric cancers are adenocarcinomas (about 90% to 95%), which develop from cells in the innermost lining of the stomach (known as the mucosa).1 Gastric cancer is the fifth most diagnosed cancer and the fifth leading cause of cancer death worldwide, with approximately 969,000 patients diagnosed and 660,000 deaths from the disease globally in 2022.4 In Japan, it is estimated there were approximately 126,000 patients diagnosed with gastric cancer and almost 44,000 deaths from the disease in 2022. 5 In the U.S., it is estimated there will be approximately 27,000 patients diagnosed with gastric cancer and almost 11,000 deaths from the disease in 2024.6 The five-year relative survival rate for patients diagnosed with gastric cancer at a distant stage is 7% in the U.S.

About esophageal cancer

Esophageal cancer is the 11th most commonly diagnosed cancer and the seventh leading cause of death from cancer worldwide.4 It is estimated there were 511,000 new cases of esophageal cancer diagnosed and about 445,000 deaths resulting from the disease worldwide in 2022.4 In Japan, it is estimated there were approximately 20,000 patients diagnosed with esophageal cancer and almost 12,000 deaths from the disease in 2022.5 In the U.S., it is estimated there will be approximately 22,000 patients diagnosed with esophageal cancer and almost 16,000 deaths from the disease in 2024.8 The five-year relative survival rate for patients diagnosed with advanced esophageal cancer is 6% in the US.9 Cancers that start in gland cells (cells that make mucus) are called adenocarcinomas and are often found in the lower third of the esophagus (lower thoracic esophagus).10 Adenocarcinoma is the most common form of esophageal cancer in the U.S. and its incidence is rapidly increasing in other parts of the world.

About LENVIMA (lenvatinib) Capsules

LENVIMA, discovered and developed by Eisai, is an orally available multiple receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. In syngeneic mouse tumor models, LENVIMA decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone. LENVIMA has been approved for the indications below.

Thyroid cancer

 Indication as monotherapy (Approved mainly in Japan, the United States, Europe, China and Asia) Japan: Unresectable thyroid cancer The United States: The treatment of patients with locally recurrent or metastatic, progressive, radioiodine-refractory differentiated thyroid cancer (DTC) Europe: The treatment of adult patients with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine (RAI)

Hepatocellular carcinoma

 Indication as monotherapy (Approved mainly in Japan, the United States, Europe, China and Asia) Japan: Unresectable hepatocellular carcinoma The United States: The first-line treatment of patients with unresectable hepatocellular carcinoma (HCC) Europe: The treatment of adult patients with advanced or unresectable hepatocellular carcinoma (HCC) who have received no prior systemic therapy

Thymic carcinoma

 Indication as monotherapy (Approved in Japan)
Japan: Unresectable thymic carcinoma

Renal cell carcinoma (In Europe, the agent was launched under the brand name Kisplyx)

 Indication in combination with everolimus (Approved mainly in the United States, Europe and Asia) The United States: The treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy Europe: The treatment of adult patients with advanced renal cell carcinoma following one prior vascular endothelial growth factor (VEGF) targeted therapy

 Indication in combination with KEYTRUDA (generic name: pembrolizumab) (Approved mainly in Japan, the United States, Europe and Asia) Japan: Radically unresectable or metastatic renal cell carcinoma The United States: The first-line treatment of adult patients with advanced renal cell carcinoma Europe: The first-line treatment of adult patients with advanced renal cell carcinoma Endometrial carcinoma

 Indication in combination with KEYTRUDA (Approved mainly in Japan, the United States, Europe and Asia) Japan: Unresectable, advanced or recurrent endometrial carcinoma that progressed after cancer chemotherapy The United States: The treatment of patients with advanced endometrial carcinoma (EC) that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation Europe: The treatment of adult patients with advanced or recurrent endometrial carcinoma (EC) who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and are not candidates for curative surgery.

About KEYTRUDA (pembrolizumab) Injection, 100mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

On January 24, 2025 Clarity Pharmaceuticals (ASX: CU6) ("Clarity" or "Company"), a clinical-stage radiopharmaceutical company with a mission to develop next-generation products that improve treatment outcomes for children and adults with cancer, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation (FTD) for 64Cu-SAR-bisPSMA for positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA) positive prostate cancer lesions in patients with biochemical recurrence (BCR) of prostate cancer following definitive therapy (Press release, Clarity Pharmaceuticals, JAN 24, 2025, View Source [SID1234649847]).

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This milestone builds on Clarity’s earlier receipt of an FTD for 64Cu-SAR-bisPSMA in patients with suspected metastasis of prostate cancer who are candidates for initial definitive therapy1. These 2 FTDs enable the Company to accelerate the development of its comprehensive diagnostic program with this product.

The FDA’s FTD is designed to expedite the development and regulatory review of novel drugs addressing serious conditions with significant unmet medical needs. For 64Cu-SAR-bisPSMA, it provides a number of product development advantages. The designation paves the way for a faster review process once Clarity submits its product approval applications. Additionally, it enables more frequent communication with the FDA, allowing for rapid resolution of queries during development. Furthermore, Clarity can submit completed sections of its application as they are ready, rather than waiting for the entire package to be finished before it can be lodged with the FDA. These benefits would reduce the review time needed to bring this innovative prostate cancer imaging agent to market, potentially improving diagnosis and treatment planning for patients sooner.

The FTD submission highlighted several advantages of 64Cu-SAR-bisPSMA over currently approved PSMA PET agents due to the bivalent structure of bisPSMA and the longer half-life of 64Cu (12.7 hours vs. <2 hours for 18F and 68Ga). These advantages include improved diagnostic performance, flexible imaging schedule and broader availability. The data for this FTD submission was primarily focused on the results of the Phase I/II COBRA study, which assessed the safety and diagnostic performance of 64Cu-SAR-bisPSMA in detecting prostate cancer in patients with BCR of their disease who had a negative or equivocal standard of care (SOC) scan at study entry. Advantages have been shown with same-day and next-day imaging, however, the standout was next-day 64Cu-SAR-bisPSMA PET imaging, showing localised disease in up to 80% of participants and detecting lesions as small as 2 mm. This compares favourably against the current SOC PSMA PET agents, with which the detection of lesions smaller than 5 mm is challenging. The number of lesions detected by 64Cu-SAR-bisPSMA on next-day imaging almost doubled compared to same-day imaging, and 64Cu-SAR-bisPSMA was also able to identify more lesions at much earlier timepoints (Figure 1) compared to approved PSMA PET agents.The COBRA trial paved the way for Clarity’s second diagnostic registrational trial, AMPLIFY, and an investigator-initiated trial (IIT) Co-PSMA, led by Prof Louise Emmett at St Vincent’s Hospital Sydney. The AMPLIFY trial will be a non-randomised, single-arm, open-label, multi-centre, Phase III diagnostic clinical trial of 64Cu-SAR-bisPSMA PET in approximately 220 participants with rising or detectable PSA after initial definitive treatment. As a pivotal trial, the final study results are intended to provide sufficient evidence to support an application to the FDA for approval of 64Cu-SAR-bisPSMA as a new diagnostic imaging agent in prostate cancer in patients with BCR. The Co-PSMA IIT will aim to build on the evidence generated so far, evaluating the diagnostic performance of 64Cu-SAR-bisPSMA in comparison to SOC 68Ga-PSMA-11 for the detection of recurrent prostate cancer lesions with curative intent.

Clarity’s Executive Chairperson, Dr Alan Taylor, commented, "Receiving the second FTD for 64Cu-SAR-bisPSMA and well within the 60-day period following our application submission, reserved by the U.S. FDA for review, is yet another significant milestone in our bisPSMA program. This highlights the high unmet need for novel diagnostics in prostate cancer and the high quality of data we presented to the FDA.

"The market for first-generation diagnostic PSMA PET today is approximately US$2 billion (AU$3.2 billion) in the U.S. alone, with little differentiation between products. It is expected to further grow to US$3 billion (AU$4.75 billion) by 2029. The development pipeline of new products coming to market, outside of 64Cu-SAR-bisPSMA, also offers no differentiation from the existing offering, with some new entrants commercialising the unpatented 68Ga-PSMA-11 agent, which has been capitalised on by three separate groups already.

"Being able to now fast-track the development of 64Cu-SAR-bisPSMA for patients with BCR as well as for patients prior to initial definitive therapy is incredibly exciting. The news is especially timely as we are actively preparing to commence recruitment for our second registrational trial, AMPLIFY, in the coming months. The designation will allow us to work closely with the FDA to facilitate the development process and accelerate the approval of what could become a best-in-class diagnostic.

"The dual targeting structure of bisPSMA enables increased uptake and retention of the product in the lesions, while the longer half-life of copper-64 provides greater flexibility with imaging scheduling, including next-day imaging (something that gallium-68 and fluorine-18 based products cannot support). When combined, these features make 64Cu-SAR-bisPSMA stand out from its competitors who are known to have issues with sensitivity. We have seen 2-3 times higher uptake in prostate cancer lesions and the identification of more lesions using 64Cu-SAR-bisPSMA compared to 68Ga-PSMA-11 in pre-prostatectomy patients in our PROPELLER study. The COBRA trial results showed great diagnostic performance in the BCR setting, with lesions identified by 64Cu-SAR-bisPSMA in the 2-mm range and visualised many months before SOC PSMA PET agents are able detect them.

"Not only are we developing a product that may have improved diagnostic performance compared to SOC PSMA PET agents, but the longer half-life of copper-64 also enables a longer shelf-life of 64Cu-SAR-bisPSMA than currently used diagnostic radiopharmaceuticals, allowing for centralised manufacture and wider distribution. These attributes have the potential to reduce disparities in prostate cancer care and ensure that most patients, regardless of geographic location, can benefit from the latest advances in diagnostic technology.

"This designation highlights the unique opportunity for 64Cu-SAR-bisPSMA in this very large market by addressing the limitations of the current-generation diagnostic radiopharmaceuticals and providing patients with prostate cancer with a more accurate diagnosis leading to more optimal treatment options. As such, we are fully committed to advancing the development of this best-in-class product to address the critical need for more accurate and accessible diagnostic tools in prostate cancer management."

About SAR-bisPSMA
SAR-bisPSMA derives its name from the word "bis", which reflects a novel approach of connecting two PSMA-targeting agents to Clarity’s proprietary sarcophagine (SAR) technology that securely holds copper isotopes inside a cage-like structure, called a chelator. Unlike other commercially available chelators, the SAR technology prevents copper leakage into the body. SAR-bisPSMA is a Targeted Copper Theranostic (TCT) that can be used with isotopes of copper-64 (Cu-64 or 64Cu) for imaging and copper-67 (Cu-67 or 67Cu) for therapy.

About Prostate Cancer
Prostate cancer is the second most common cancer diagnosed in men globally and the fifth leading cause of cancer death in men worldwide4. Prostate cancer is the second-leading causes of cancer death in American men. The American Cancer Institute estimates in 2025 there will be about 313,780 new cases of prostate cancer in the U.S. and around 35,770 deaths from the disease.

On January 23, 2025 Ascentage Pharma (Nasdaq: AAPG) (HKEX: 6855) reported the pricing of its U.S. initial public offering of 7,325,000 American depositary shares ("ADSs"), at a public offering price of $17.25 per ADS, before underwriting discounts and commissions (Press release, Ascentage Pharma, JAN 23, 2025, View Source [SID1234650021]). Each ADS represents four ordinary shares of Ascentage Pharma. The gross proceeds from the offering, before deducting underwriting discounts and commissions and other offering expenses payable by Ascentage Pharma, are expected to be approximately $126.4 million. In addition, Ascentage Pharma has granted the underwriters a 30-day option to purchase up to an additional 1,098,750 ADSs at the initial public offering price, less underwriting discounts and commissions. The ADSs are expected to begin trading on the Nasdaq Global Market on January 24, 2025, under the ticker "AAPGV" on a "when-issued" basis, and on January 27, 2025, under the ticker symbol "AAPG" for "regular-way" trading. The offering is expected to close on January 28, 2025, subject to customary closing conditions.

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J.P. Morgan and Citigroup are acting as joint book-running managers for the offering.

A registration statement relating to these securities was declared effective by the Securities and Exchange Commission on January 23, 2025. The offering will be made only by means of a prospectus. Copies of the prospectus relating to the offering may be obtained, from: J.P. Morgan Securities LLC, c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717, or by email at [email protected] and [email protected], and Citigroup, c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717, or by telephone at 1-800-831-9146.

This press release shall not constitute an offer to sell or a solicitation of an offer to buy, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation, or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.