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Japan’s Ministry of Health, Labour and Welfare Approves PADCEV™ (enfortumab vedotin) with KEYTRUDA® (pembrolizumab) for First-Line Treatment of Radically Unresectable Urothelial Carcinoma

On September 24, 2024 Astellas Pharma Inc. (TSE:4503, President and CEO: Naoki Okamura, "Astellas") reported that Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved PADCEV (enfortumab vedotin [genetical recombination]) with MSD’s KEYTRUDA (pembrolizumab [genetical recombination]) as a combination therapy for the first-line treatment of adult patients with radically unresectable urothelial carcinoma (Press release, Astellas, SEP 24, 2024, View Source,-Labour-and-Welfare-Approves-PADCEV-TM-enfortumab-vedotin-with-KEYTRUDA-R-pembrolizumab-for-First-Line-Treatment-of-Radically-Unresectable-Urothelial-Carcinoma [SID1234646833]). This is the first approved combination treatment for radically unresectable urothelial cancer in Japan to offer an alternative to platinum-containing chemotherapy, the current standard of care for first-line treatment.

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In Japan, bladder cancer is the 9th most common cancer, with over 34,500 new cases diagnosed and 11,000 deaths reported from the disease in 2022.3 Particularly poor outcomes are associated with the latter stages of the disease, with global five-year survival rates of 39% and 8% for locally advanced and metastatic urothelial cancer, respectively.4

The approval by the MHLW was supported by results from the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39) which explored the efficacy and safety of enfortumab vedotin in combination with pembrolizumab in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC). Results showed that the treatment combination resulted in a median overall survival of 31.5 months (95% CI: 25.4-NR) compared to 16.1 months (95% CI: 13.9-18.3) with platinum-containing chemotherapy, representing a 53% reduction in risk of death (Hazard Ratio [HR]=0.47; 95% Confidence Interval [CI]: 0.38-0.58; P<0.00001). The median progression-free survival of 12.5 months (95% CI: 10.4-16.6) with the combination compared to 6.3 months (95% CI: 6.2-6.5) with chemotherapy represents a 55% reduction in the risk of cancer progression or death (HR=0.45; 95% CI: (0.38-0.54); P<0.00001). The safety results in EV-302 are consistent with those previously reported for this combination in EV-103 in cisplatin-ineligible patients with la/mUC. The most common (≥3%) Grade 3 or higher adverse events (AEs) related to treatment with enfortumab vedotin in combination with pembrolizumab were maculo-papular rash, hyperglycemia, neutropenia, peripheral sensory neuropathy, diarrhea, and anemia. No new safety issues were identified. During the EV-302 trial, approximately 30% of patients completed treatment with chemotherapy and then went on to receive maintenance therapy with avelumab, a PD-L1 inhibitor, which is reflective of current real world clinical practice.1 Results were presented at the 2023 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress and published in the New England Journal of Medicine.1

Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas
"Today’s approval by Japan’s MHLW expands the benefits of treatment with enfortumab vedotin in combination with pembrolizumab to patients living with radically unresectable urothelial carcinoma in Japan. These patients will now have an alternative to platinum-containing chemotherapy to treat this devastating disease, helping to improve patient outcomes, extend lives and give further hope to the patients and families that we serve."

In addition to this latest approval, enfortumab vedotin in combination with pembrolizumab was approved by the European Commission in August 2024 for the first-line treatment of adult patients with unresectable or metastatic urothelial cancer, who are eligible for platinum-containing chemotherapy. Furthermore, in December 2023, the U.S. Food and Drug Administration approved the use of the combination therapy for adult patients with locally advanced or metastatic urothelial cancer.

Astellas has already reflected the impact from the approval for enfortumab vedotin in Japan in its financial forecast for the current fiscal year ending March 31, 2025.

About EV-302
The EV-302 trial is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated la/mUC. The study enrolled 886 patients with previously untreated la/mUC who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status. Patients were randomized to receive either enfortumab vedotin in combination with pembrolizumab or platinum-containing chemotherapy. The dual primary endpoints of this trial are OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Select secondary endpoints include ORR per RECIST v1.1 by BICR, DOR per RECIST v1.1 by BICR, and safety.1

The EV-302 trial is part of an extensive clinical program evaluating this combination in multiple stages of urothelial cancer and other solid tumors. Findings from EV-302 were presented at the 2023 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress and published in the New England Journal of Medicine.1

About Bladder and Urothelial Cancer
Urothelial cancer, or bladder cancer, begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs.5 Urothelial cancer accounts for 90% of global bladder cancers and can also be found in the renal pelvis, ureter, and urethra.6,7 If bladder cancer has spread to surrounding organs or muscles, it is called locally advanced disease.8 If the cancer has spread to other parts of the body, it is called metastatic disease.9 Globally, approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.10

About PADCEV (enfortumab vedotin [genetical recombination])
PADCEV (enfortumab vedotin [genetical recombination]) is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.11,12 Non-clinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to Nectin-4-expressing cells, followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).11

PADCEV is indicated in Japan as monotherapy for the treatment of adult patients with radically unresectable urothelial carcinoma that has progressed after anti-cancer chemotherapy, and in combination with KEYTRUDA (pembrolizumab) for the first-line treatment of adult patients with radically unresectable urothelial carcinoma.13

Ongoing Investigational Trials
EV-302 (NCT04223856) is an open-label, randomized, controlled Phase 3 trial, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status.

EV-103 (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter Phase 1b/2 trial investigating enfortumab vedotin alone or in combination with pembrolizumab and/or chemotherapy in first- or second-line settings in patients with la/mUC and in patients with muscle-invasive bladder cancer (MIBC).

Enfortumab vedotin in combination with pembrolizumab is being investigated in an extensive program in multiple stages of urothelial cancer, including two Phase 3 clinical trials in MIBC in EV-304 (NCT04700124, also known as KEYNOTE-B15) and EV-303 (NCT03924895, also known as KEYNOTE-905). The use of enfortumab vedotin in combination with pembrolizumab in second-line urothelial cancer and MIBC has not been proven safe or effective.

EV-203 (NCT04995419) is a Phase 2, multicenter, single-arm bridging trial in China designed to evaluate the efficacy, safety, and pharmacokinetic performance of enfortumab vedotin as treatment for patients in China. A total of 40 patients were enrolled in the trial.

EV-104 (NCT05014139) is a Phase 1 trial exploring enfortumab vedotin in patients with non-muscle invasive bladder cancer (NMIBC). The trial will be conducted in two-parts, assessing dose escalation and dose expansion with enfortumab vedotin when administered intravesically as a monotherapy.

EV-202 (NCT04225117) is an ongoing, multi-cohort, open-label, multicenter Phase 2 trial investigating enfortumab vedotin alone in patients with previously treated advanced solid tumors. This trial also has a cohort that is investigating enfortumab vedotin in combination with pembrolizumab in patients with previously untreated recurrent / metastatic head and neck squamous cell carcinoma.

Important Safety Information
For important Safety Information for PADCEV, please see the Package Insert.

PDX Pharma was awarded a new grant from NCI

On September 25, 2024 PDX Pharmaceuticals reported that it has received a $250,000 SBIR Commercialization Readiness Program (CRP) grant (SB1CA287735) from the National Cancer Institute (NCI) to advance ARAC-02, our next-gen immunotherapy for non-small cell lung cancer (NSCLC) (Press release, PDX Pharmaceuticals, SEP 23, 2024, View Source [SID1234646860]). This funding supports intellectual property (IP) protection of our core nanotechnology (Pdx-NP) and ARAC-02, as well as the initiation of a GMP-compliant manufacturing campaign. The goal is to enhance commercialization readiness and prepare for clinical trials. Huge congrats to our team, and a big thank you to the NCI for their continued support!

Repare Therapeutics Announces New Data Underscoring Need for Additional Treatment Solutions for Patients with Metastatic Gynecologic Cancers

On September 23, 2024 Repare Therapeutics Inc. ("Repare" or the "Company") (Nasdaq: RPTX), a leading clinical-stage precision oncology company, reported new data on Friday highlighting the impact of alterations in FBXW7, PPP2R1A and CCNE1 in patients with metastatic ovarian and endometrial cancers based on an analysis in approximately 2,000 patients from Cancer Genome Atlas Research Network and Memorial Sloan Kettering’s Metastatic Events and Tropisms (Press release, Repare Therapeutics, SEP 23, 2024, View Source [SID1234646830]).

The poster presentation was shared at the American Association of Cancer Research’s (AACR) (Free AACR Whitepaper) 15th Annual Ovarian Cancer Research Symposium in Seattle, underscores inherent chemotherapy resistance and the lack of treatment options for metastatic gynecologic cancer patients with these biomarkers.

"Patients with recurrent ovarian and endometrial cancers are already at a disadvantage when it comes to treatment options," said Maria Koehler, MD, PhD, Executive Vice President and Chief Medical Officer of Repare. "These new data highlight the urgent need for innovative therapeutic approaches to address the specifically poor prognosis associated with FBXW7, PPP2R1A and CCNE1 alterations treated with standard of care-based chemotherapy. We look forward to reporting data from our MYTHIC dose expansion trial evaluating lunresertib in combination with camonsertib in patients with ovarian and endometrial cancers with these biomarkers in the fourth quarter of 2024."

Repare Therapeutics’ Phase 1 MYTHIC clinical trial (NCT04855656) is studying the combination of lunresertib, a first-in-class oral small molecule PKMYT1 inhibitor, and camonsertib, a potential best-in-class oral small molecule ATR inhibitor, in patients harboring lunresertib-sensitizing biomarkers (Lunre BM), including CCNE1 amplifications or mutations in FBXW7 or PPP2R1A. While CCNE1 amplifications occur in approximately 30% of platinum-resistant ovarian cancers,1-2 and are well established as a poor prognostic indicator in ovarian cancer,3-6 little is known about other Lunre BM in ovarian and endometrial cancers.

Ovarian Cancer:

The presence of Lunre BM (alterations in CCNE1, PPP2R1A, or FBXW7) in ovarian cancer patients (n=1,029) is linked to a substantially lower survival rate compared to those without these biomarkers, underscoring their prognostic significance:

Median overall survival (mOS) for patients with these biomarkers (Lunre BM+) is 26 months (95% CI, 18-38), compared to 36 months (95% CI, 30-43) for patients without these biomarkers (Lunre BM-; HR = 1.46 [95% CI, 1.14-1.87], p=0.003), a 28% decrease in mOS
Endometrial Cancer:

Endometrial cancer patients (n=895) with biomarkers CCNE1, PPP2R1A, and FBXW7 demonstrate poorer survival outcomes, which are influenced by their association with high-risk histologies and genetic alterations:

Median overall survival (mOS) for patients with these biomarkers (Lunre BM+) is 30 months (95% CI, 24-38), compared to 41 months (95% CI, 31-60) for patients without these biomarkers (Lunre BM-; HR = 1.29 [95% CI, 1.03-1.60], p=0.024), a 27% decrease in mOS
The presence of these biomarkers also correlates with high-risk histologies (uterine carcinosarcoma and uterine serous carcinoma) and p53 mutant genotypes, well known for adverse prognosis

Antengene Announces XPOVIO® (selinexor) Approved for Commercialization in Thailand

On September 23, 2024 Antengene Corporation Limited ("Antengene", SEHK: 6996.HK), a leading innovative, commercial-stage global biopharmaceutical company dedicated to discovering, developing and commercializing first-in-class and/or best-in-class medicines for cancer, reported that the Thailand Food and Drug Administration has approved a New Drug Application (NDA) for XPOVIO (selinexor) for two indications (Press release, Antengene, SEP 23, 2024, View Source [SID1234646829]): (1) In combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma(MM) who have received at least one prior therapy; and (2) in combination with dexamethasone for the treatment of adult patients with MM who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, two immunomodulatory agents and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy.

With a novel mechanism of action, XPOVIO is the world’s first approved orally-available, selective XPO1 inhibitor, which has already been approved in nine markets in APAC. This successful approval for XPOVIO in Thailand will introduce novel therapies to the clinical management of patients with MM in Thailand, benefiting many patients and their families in the country. To date, XPOVIO has also been included in national health insurance or reimbursement schemes in the mainland of China, Australia, Singapore and South Korea.

The ASEAN region, with its steady economic growth and a population exceeding 600 million, has become a significant potential market for global biomedical development. The accelerating aging population in ASEAN has increased the overall disease burden on patients and local communities, leading to a growing demand for novel therapeutics. Fulfilling its commitment to enhancing the health and well-being of the ASEAN population, Antengene has successfully obtained NDA approvals for XPOVIO in Malaysia in August and very recently in Thailand, and expects XPOVIO to be approved in Indonesia in the second half of 2024. Looking ahead, the company aims to introduce more innovative medicines to the ASEAN market, bringing improved healthcare to more patients in the region.

While bringing XPOVIO to more APAC markets, Antengene is also striving to expand the indications of XPOVIO. Leveraging the drug’s novel mechanism of action, Antengene is currently developing multiple combination regimens of XPOVIO for the treatment of various indications including myelofibrosis (MF), and endometrial cancer.

About XPOVIO (selinexor)

XPOVIO is the world’s first approved orally-available, selective inhibitor of the nuclear export protein XPO1. It offers a novel mechanism of action, synergistic effects in combination regimens, fast onset of action, and durable responses.

By blocking the nuclear export protein XPO1, XPOVIO can promote the intranuclear accumulation and activation of tumor suppressor proteins and growth regulating proteins, and down-regulate the levels of multiple oncogenic proteins. XPOVIO delivers its antitumor effects through three mechanistic pathways: 1) exerting antitumor effects by inducing the intranuclear accumulation of tumor suppressor proteins; 2) reducing the level of oncogenic proteins in the cytoplasm by inducing the intranuclear accumulation of oncogenic mRNAs; 3) restoring hormone sensitivity by activating the glucocorticoid receptors (GR) pathway. To utilize its unique mechanism of actions, XPOVIO is being evaluated for use in multiple combination regimens in a range of indications. At present, Antengene is conducting multiple clinical studies of XPOVIO in the mainland of China for the treatment of relapsed/refractory hematologic malignancies and solid tumors (3 of these studies are being jointly conducted by Antengene and Karyopharm Therapeutics Inc. [Nasdaq:KPTI]).

Ryvu Therapeutics to present ONCO Prime platform at the 6th Annual RAS-Targeted Drug Development Summit

On September 23, 2024 Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, reported that it will present its ONCO Prime drug discovery platform at the 6th Annual RAS-Targeted Drug Development Summit, a leading global end-to-end RAS therapies forum, which will take place on September 24-26 in Boston, MA (Press release, Ryvu Therapeutics, SEP 23, 2024, View Source [SID1234646827]).

ONCO Prime is a cutting-edge drug discovery platform identifying novel synthetic lethal targets using patient-derived primary cell cultures. The platform comprises of new cancer models with the optimal ratio of translational potential and high-throughput feasibility. By using patient-derived cells, the ONCO Prime platform uses patients’ medical history combined with histopathological, genomic, and transcriptomic data to enable the correlation of clinical and molecular data. Initial platform screens have identified potentially novel drug targets in KRAS-mutant colorectal cancer (CRC). Additionally, the platform has broad applicability across multiple tumor types, and additional screens in other major tumor areas are ongoing.

Krzysztof Brzózka, Ph.D., Chief Scientific Officer and Executive Vice President of Ryvu Therapeutics, said:

– "We are proud that, within a short time since its development began in mid-2023, the ONCO Prime platform has already identified novel targets in KRAS-mutant cells – targets overlooked by conventional immortalized CRC cell lines. This achievement highlights the platform’s unique capability, and we’re excited to discuss its implications with the international RAS-focused community."

ONCO Prime is co-financed by the European Union under the Operational Programme European Funds for Modern Economy 2021-2027. Project title: "ONCO Prime: new possibilities for personalised anti-cancer therapy based on patient-derived primary cell cultures, omics characterisation, and functional assays". Grant Agreement no: FENG.01.01-IP.02-0095/23. This co-financing is being administered through the Polish Agency for Enterprise Development (PARP). Ryvu expects to receive PLN 26.3 million (approximately USD 6.6 million) in grant funding over five years to support ONCO Prime.
The 6th Annual RAS-Targeted Drug Development Summit is the central hub dedicated to every aspect of RAS discovery and development, from discovery and clinical development to commercialization. It equips 150+ global RAS leaders with the means to create effective RAS therapies for better patient outcomes.