On March 28, 2024 Astellas Pharma Inc. (TSE:4503, President and CEO: Naoki Okamura, "Astellas") reported that on March 27, 2024 the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) has accepted the supplemental Biologics License Application (sBLA) for enfortumab vedotin with KEYTRUDA (pembrolizumab) as a combination therapy for the first-line treatment of adult patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) (Press release, Astellas, MAR 28, 2024, View Source [SID1234641554]). If approved, enfortumab vedotin with KEYTRUDA has the potential to change the treatment paradigm, becoming the first combination treatment to offer an alternative to platinum-containing chemotherapy, the current standard of care in first-line la/mUC.

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Urothelial cancer (UC) encompasses cancers of both the lower urinary tract (bladder and urethra) and upper tract (ureter and renal pelvis), with disease that originates in the lower tract accounting for 90% to 95% of all UC cases.ⅰ,ⅱ Globally, approximately 614,000 new cases of bladder cancer and approximately 220,000 deaths are reported annually.ⅲ It is estimated that approximately 93,000 people in China were diagnosed with bladder cancer and approximately 41,000 deaths were reported in 2022.iv

Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas
"Locally advanced or metastatic urothelial cancer is a life-threatening condition in China with nearly half of those diagnosed succumbing to the disease. The CDE’s acceptance of our sBLA for enfortumab vedotin and pembrolizumab brings us one step closer to delivering a much-needed, innovative new treatment option for this patient population."

Professor Guo Jun, lead PI in China for the EV-302 trial, director of the Department of Melanoma and Urological Oncology at Beijing Cancer Hospital, executive board member of the Chinese Society Of Clinical Oncology (CSCO)
"In China, the recommended first-line treatment for advanced urothelial cancer is platinum-based chemotherapy, and there are currently no other treatments approved in the first-line setting. Given the efficacy brought by chemotherapy, alternate treatment options are extremely needed to extend survival benefits and potentially improve the prognosis of those patients. The results of the EV-302 study demonstrated that enfortumab vedotin in combination with pembrolizumab, as the first non-platinum first-line treatment, can achieve a clinically meaningful improvement in response rate, nearly double the median progression-free survival, and significantly improve the overall survival benefit of patients with locally advanced or metastatic urothelial cancer compared to chemotherapy."

The sBLA for the first-line use of this combination is based on results from the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39). The study found that the combination improved overall survival (OS) and progression-free survival (PFS) with statistically significant and clinically meaningful results in patients with previously untreated la/mUC compared to platinum-containing chemotherapy. The safety results were consistent with those previously reported with this combination, and no new safety issues were identified.

The NMPA is also reviewing enfortumab vedotin as a treatment for patients with locally advanced or metastatic urothelial cancer (la/mUC) who received prior treatment with a PD-1/L1 inhibitor and platinum-based chemotherapy.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency is reviewing the enfortumab vedotin in combination with pembrolizumab therapy, as well as Japan’s Ministry of Health, Labour and Welfare (MHLW). The U.S. Food and Drug Administration approved the combination therapy in December 2023.

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.

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 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023 in October 2023.

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.ⅴ

If bladder cancer has spread to surrounding organs or muscles, it is called locally advanced disease. If the cancer has spread to other parts of the body, it is called metastatic disease. ⅵ

Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra.ⅲ

Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.ⅶ

Ongoing Investigational Trials
The EV-302 trial (NCT04223856) 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 locally advanced or metastatic urothelial cancer (la/mUC) who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status.

The EV-103 trial (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter Phase 1b/2 study 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.

The EV-202 trial (NCT04225117) is an ongoing, multi-cohort, open-label, multicenter Phase 2 study investigating enfortumab vedotin alone in patients with previously treated advanced solid tumors. This study 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.

The EV-203 trial (NCT04995419) is a Phase 2, multicenter, single-arm bridging study 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 study.

About Enfortumab Vedotin
Enfortumab vedotin 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. ⅷ Nonclinical 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). ⅸ

PADCEV (enfortumab vedotin-ejfv) U.S. Indication & Important Safety Information

BOXED WARNING: SERIOUS SKIN REACTIONS

PADCEV can cause severe and fatal cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later.

Closely monitor patients for skin reactions.

Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions.

Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.

Indication

PADCEV, in combination with pembrolizumab, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC).

PADCEV, as a single agent, is indicated for the treatment of adult patients with locally advanced or mUC who:

have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or

are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Skin reactions Severe cutaneous adverse reactions, including fatal cases of SJS or TEN occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later. Skin reactions occurred in 70% (all grades) of the 564 patients treated with PADCEV in combination with pembrolizumab in clinical trials. When PADCEV was given in combination with pembrolizumab, the incidence of skin reactions, including severe events, occurred at a higher rate compared to PADCEV as a single agent. The majority of the skin reactions that occurred with combination therapy included maculo-papular rash, macular rash and papular rash. Grade 3-4 skin reactions occurred in 17% of patients (Grade 3: 16%, Grade 4: 1%), including maculo-papular rash, bullous dermatitis, dermatitis, exfoliative dermatitis, pemphigoid, rash, erythematous rash, macular rash, and papular rash. A fatal reaction of bullous dermatitis occurred in one patient (0.2%). The median time to onset of severe skin reactions was 1.7 months (range: 0.1 to 17.2 months). Skin reactions led to discontinuation of PADCEV in 6% of patients.

Skin reactions occurred in 58% (all grades) of the 720 patients treated with PADCEV as a single agent in clinical trials. Twenty-three percent (23%) of patients had maculo-papular rash and 34% had pruritus. Grade 3-4 skin reactions occurred in 14% of patients, including maculo-papular rash, erythematous rash, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. The median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 8 months). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=75), 24% of patients restarting at the same dose and 24% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 3.1% of patients.

Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated. For persistent or recurrent Grade 2 skin reactions, consider withholding PADCEV until Grade ≤1. Withhold PADCEV and refer for specialized care for suspected SJS, TEN or for Grade 3 skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.

Hyperglycemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with PADCEV. Patients with baseline hemoglobin A1C ≥8% were excluded from clinical trials. In clinical trials of PADCEV as a single agent, 17% of the 720 patients treated with PADCEV developed hyperglycemia of any grade; 7% of patients developed Grade 3-4 hyperglycemia (Grade 3: 6.5%, Grade 4: 0.6%). Fatal events of hyperglycemia and DKA occurred in one patient each (0.1%). The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. The median time to onset of hyperglycemia was 0.5 months (range: 0 to 20 months). Hyperglycemia led to discontinuation of PADCEV in 0.7% of patients. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. Of the patients who initiated insulin therapy for treatment of hyperglycemia, 66% (23/35) discontinued insulin at the time of last evaluation. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV.

Pneumonitis/Interstitial Lung Disease (ILD) Severe, life-threatening or fatal pneumonitis/ILD occurred in patients treated with PADCEV. When PADCEV was given in combination with pembrolizumab, 10% of the 564 patients treated with combination therapy had pneumonitis/ILD of any grade and 4% had Grade 3-4. A fatal event of pneumonitis/ILD occurred in two patients (0.4%). The incidence of pneumonitis/ILD, including severe events, occurred at a higher rate when PADCEV was given in combination with pembrolizumab compared to PADCEV as a single agent. The median time to onset of any grade pneumonitis/ILD was 4 months (range: 0.3 to 26 months).

In clinical trials of PADCEV as a single agent, 3% of the 720 patients treated with PADCEV had pneumonitis/ILD of any grade and 0.8% had Grade 3-4. The median time to onset of any grade pneumonitis/ILD was 2.9 months (range: 0.6 to 6 months).

Monitor patients for signs and symptoms indicative of pneumonitis/ILD such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations. Withhold PADCEV for patients who develop Grade 2 pneumonitis/ILD and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis/ILD.

Peripheral neuropathy (PN) When PADCEV was given in combination with pembrolizumab, 67% of the 564 patients treated with combination therapy had PN of any grade, 36% had Grade 2 neuropathy, and 7% had Grade 3 neuropathy. The incidence of PN occurred at a higher rate when PADCEV was given in combination with pembrolizumab compared to PADCEV as a single agent. The median time to onset of Grade ≥2 PN was 6 months (range: 0.3 to 25 months).
PN occurred in 53% of the 720 patients treated with PADCEV as a single agent in clinical trials including 38% with sensory neuropathy, 8% with muscular weakness and 7% with motor neuropathy. Thirty percent of patients experienced Grade 2 reactions and 5% experienced Grade 3-4 reactions. PN occurred in patients treated with PADCEV with or without preexisting PN. The median time to onset of Grade ≥2 PN was 4.9 months (range: 0.1 to 20 months). Neuropathy led to treatment discontinuation in 6% of patients.

Monitor patients for symptoms of new or worsening PN and consider dose interruption or dose reduction of PADCEV when PN occurs. Permanently discontinue PADCEV in patients who develop Grade ≥3 PN.

Ocular disorders were reported in 40% of the 384 patients treated with PADCEV as a single agent in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy. Dry eye symptoms occurred in 30% of patients, and blurred vision occurred in 10% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.7 months (range: 0 to 30.6 months). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.

Infusion site extravasation Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 720 patients treated with PADCEV as a single agent in clinical trials, 1% of patients experienced skin and soft tissue reactions, including 0.3% who experienced Grade 3-4 reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. Two patients (0.3%) developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.

Embryo-fetal toxicity PADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.

ADVERSE REACTIONS

Most common adverse reactions, including laboratory abnormalities (≥20%) (PADCEV in combination with pembrolizumab) Increased aspartate aminotransferase (AST), increased creatinine, rash, increased glucose, PN, increased lipase, decreased lymphocytes, increased alanine aminotransferase (ALT), decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection and decreased platelets.

Most common adverse reactions, including laboratory abnormalities (≥20%) (PADCEV monotherapy) Increased glucose, increased AST, decreased lymphocytes, increased creatinine, rash, fatigue, PN, decreased albumin, decreased hemoglobin, alopecia, decreased appetite, decreased neutrophils, decreased sodium, increased ALT, decreased phosphate, diarrhea, nausea, pruritus, increased urate, dry eye, dysgeusia, constipation, increased lipase, decreased weight, decreased platelets, abdominal pain, dry skin.

EV-302 Study: 440 patients with previously untreated la/mUC (PADCEV in combination with pembrolizumab)

Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab. The most common serious adverse reactions (≥2%) were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Fatal adverse reactions occurred in 3.9% of patients treated with PADCEV in combination with pembrolizumab including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%).
Adverse reactions leading to discontinuation of PADCEV occurred in 35% of patients. The most common adverse reactions (≥2%) leading to discontinuation of PADCEV were PN (15%), rash (4.1%) and pneumonitis/ILD (2.3%). Adverse reactions leading to dose interruption of PADCEV occurred in 73% of patients. The most common adverse reactions (≥2%) leading to dose interruption of PADCEV were PN (22%), rash (16%), COVID-19 (10%), diarrhea (5%), pneumonitis/ILD (4.8%), fatigue (3.9%), hyperglycemia (3.6%), increased ALT (3%) and pruritus (2.5%). Adverse reactions leading to dose reduction of PADCEV occurred in 42% of patients. The most common adverse reactions (≥2%) leading to dose reduction of PADCEV were rash (16%), PN (13%) and fatigue (2.7%).

EV-103 Study: 121 patients with previously untreated la/mUC who were not eligible for cisplatin-containing chemotherapy (PADCEV in combination with pembrolizumab)

Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab; the most common (≥2%) were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), sepsis (3.3%), pneumonia (3.3%), hematuria (3.3%), pneumonitis/ILD (3.3%), urinary retention (2.5%), diarrhea (2.5%), myasthenia gravis (2.5%), myositis (2.5%), anemia (2.5%), and hypotension (2.5%). Fatal adverse reactions occurred in 5% of patients treated with PADCEV in combination with pembrolizumab, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis/ILD (0.8%). Adverse reactions leading to discontinuation of PADCEV occurred in 36% of patients; the most common (≥2%) were PN (20%) and rash (6%). Adverse reactions leading to dose interruption of PADCEV occurred in 69% of patients; the most common (≥2%) were PN (18%), rash (12%), increased lipase (6%), pneumonitis/ILD (6%), diarrhea (4.1%), acute kidney injury (3.3%), increased ALT (3.3%), fatigue (3.3%), neutropenia (3.3%), urinary tract infection (3.3%), increased amylase (2.5%), anemia (2.5%), COVID-19 (2.5%), hyperglycemia (2.5%), and hypotension (2.5%). Adverse reactions leading to dose reduction of PADCEV occurred in 45% of patients; the most common (≥2%) were PN (17%), rash (12%), fatigue (5%), neutropenia (5%), and diarrhea (4.1%).

EV-301 Study: 296 patients previously treated with a PD-1/L1 inhibitor and platinum-based chemotherapy (PADCEV monotherapy)

Serious adverse reactions occurred in 47% of patients treated with PADCEV; the most common (≥2%) were urinary tract infection, acute kidney injury (7% each), and pneumonia (5%). Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis/ILD, and pelvic abscess (0.3% each). Adverse reactions leading to discontinuation occurred in 17% of patients; the most common (≥2%) were PN (5%) and rash (4%). Adverse reactions leading to dose interruption occurred in 61% of patients; the most common (≥4%) were PN (23%), rash (11%), and fatigue (9%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common (≥2%) were PN (10%), rash (8%), decreased appetite, and fatigue (3% each).

EV-201, Cohort 2 Study: 89 patients previously treated with a PD-1/L1 inhibitor and not eligible for cisplatin-based chemotherapy (PADCEV monotherapy)

Serious adverse reactions occurred in 39% of patients treated with PADCEV; the most common (≥3%) were pneumonia, sepsis, and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia, and pneumonitis/ILD (1.1% each). Adverse reactions leading to discontinuation occurred in 20% of patients; the most common (≥2%) was PN (7%). Adverse reactions leading to dose interruption occurred in 60% of patients; the most common (≥3%) were PN (19%), rash (9%), fatigue (8%), diarrhea (5%), increased AST, and hyperglycemia (3% each). Adverse reactions leading to dose reduction occurred in 49% of patients; the most common (≥3%) were PN (19%), rash (11%), and fatigue (7%).

DRUG INTERACTIONS

Effects of other drugs on PADCEV (Dual P-gp and Strong CYP3A4 Inhibitors)
Concomitant use with dual P-gp and strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with dual P-gp and strong CYP3A4 inhibitors.

SPECIFIC POPULATIONS

Lactation Advise lactating women not to breastfeed during treatment with PADCEV and for 3 weeks after the last dose.

Hepatic impairment Avoid the use of PADCEV in patients with moderate or severe hepatic impairment.

For more information, please see the U.S. full Prescribing Information including BOXED WARNING for PADCEV here.

On March 28, 2024 Affimed N.V. (Nasdaq: AFMD) ("Affimed" or the "Company"), a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer, reported financial results and provided an update on clinical and corporate progress for the year ended December 31, 2023 (Press release, Affimed, MAR 28, 2024, View Source [SID1234641553]).

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"The clinical achievements in 2023 with our three programs, AFM24, acimtamig, and AFM28, provide a strong foundation for us to deliver on meaningful clinical milestones across the portfolio in 2024 and beyond," said Dr. Andreas Harstrick, Chief Medical Officer and interim Chief Executive Officer at Affimed. "We have seen compelling responses in treatment refractory NSCLC EGFR-wt patients and will report mature PFS data of these patients as well as response data from the NSCLC EGFR-mut cohort in the second quarter. With the LuminICE-203 study of acimtamig with AlloNK successfully launched in 2023, we are progressing toward an initial data update in the second quarter. The long-term follow-up data for study for the AFM13-104, presented at ASH (Free ASH Whitepaper), demonstrating that approximately 30% of patients remain in remission beyond 1 year, have further enhanced our confidence in the therapeutic potential of acimtamig in combination with NK cells. Finally, AFM28 has reached the final dose level in the escalation study providing the basis for continued development. With all three clinical programs moving forward, we are focused on the execution of these programs confident in Affimed’s ability to fulfill our overarching mission of delivering innovative therapies to cancer patients."

Program Updates

AFM24 (EGFR/CD16A tumors)
•
As of January 4, clinical response update to the Phase 1/2a AFM24-102 trial in EGFR-wt NSCLC reported 4 confirmed responses, including 1 CR, 3 PRs, and 7 stable diseases in 15 heavily pre-treated patients, resulting in a disease control rate of 73 percent. All patients were pre-treated with platinum-based chemotherapy and checkpoint inhibitors PD [L]-1. Based on the promising results, Affimed expanded enrollment in this cohort to 40 patients.

In addition, the company continues to enroll in the EGFR-mut NSCLC cohort for a planned number of 25 patients.

Mature PFS data from the first 15 patients from the EGFR-wt cohort and response data from the EGFR-mut cohort are expected in Q2 2024.

Acimtamig (AFM13; CD30/CD16A tumors)

•
Initial safety and efficacy data from the LuminICE-203 (AFM13-203) study expected in Q2 2024. LuminICE-203 is a Phase 2 clinical study investigating acimtamig in combination with Artiva’s AlloNK cells in patients with r/r classical Hodgkin lymphoma (HL). Safety Review Committee meeting and initiation of enrollment in cohorts 3 and 4 is expected mid-April.

•
Updated Phase 1/2 AFM13-104 study data demonstrated an ORR of 97% and a CR rate of 78% in 32 patients with r/r HL, presented at ASH (Free ASH Whitepaper) 2023. As of the cutoff date, the median EFS was 9.8 months with 84% patients alive at 12 months. The median duration of response was 8.8 months. The treatment regimen continues to demonstrate a good safety and tolerability profile with no cases of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) or graft versus host disease (GVHD) of any grade. The oral presentation included a total of 42 patients enrolled, with 36 patients treated at the recommended Phase 2 dose (RP2D). All patients were heavily pretreated and refractory to their most recent line of therapy with active progressive disease at the time of enrollment.

AFM28 (CD123/CD16A)

•
Completed enrollment of the fifth cohort, recruiting patients in the sixth and final cohort in the multi-center Phase 1 open-label, dose-escalation study (AFM28-101), of AFM28 monotherapy in CD123-positive r/r AML. No dose-limiting toxicities were reported. Further clinical development of AFM28 is planned in combination with an allogeneic off-the-shelf NK cell product.

Corporate Restructuring:

•
The corporate restructuring announced earlier this year has been fully implemented.

•
The restructuring included a streamlining of operations resulting in a 50% reduction in the Company’s workforce.

•
The Company is focusing resources on advancing its clinical programs, AFM24, acimtamig, and AFM28, through the various stages of development.

Upcoming Milestones:

•
Data from the NSCLC expansion cohorts in the Phase 1/2a AFM24+atezolizumab combination study expected in Q2 2024.

•
Initial data readout from the LuminICE-203 (AFM13 combination with AlloNK NK cells) study expected in Q2 2024.

•
Further progress updates from AFM28-101 dose escalation expected in Q2 2024.

Full Year 2023 Financial Highlights

Affimed’s consolidated financial statements are prepared in accordance with International Financial Reporting Standards (IFRS) as issued by the International Accounting Standard Board (IASB). The consolidated financial statements are presented in Euros (€), the Company’s functional and presentation currency.

As of December 31, 2023, cash, cash equivalents and investments totaled €72.0 million compared to €190.3 million on December 31, 2022. Based on our current operating plan and assumptions, we anticipate that our liquidity will support operations into H2 2025.

Net cash used in operating activities for the year ended December 31, 2023, was €110.3 million compared to €104.9 million for the year ended December 31, 2022.

Total revenue for the year ended December 31, 2023, was €8.3 million compared with €41.4 million for the year ended December 31, 2022. Revenue in 2022 and 2023 predominantly relates to the Roivant and Genentech collaborations for which we have now completed the work assigned to us under the respective collaboration agreements.

Research and development expenses for the year ended December 31, 2023, were €95.0 million compared to €98.8 million in 2022.

General and administrative expenses for the year ended December 31, 2023, were €24.7 million compared to €32.1 million for the year ended December 31, 2022. The decrease was due to a decline in legal, consulting and insurance expenses, as well as share-based payment expenses.

Net finance income/costs for the year ended December 31, 2023, were €0.7 million compared to €2.1 million for the year ended December 31, 2022. Net finance income/costs are largely due to foreign exchange gains/losses related to assets denominated in U.S. dollars as a result of currency fluctuations between the U.S. dollar and Euro during the year.

The weighted number of common shares outstanding for the year ended December 31, 2023, was 14.9 million, adjusted to reflect the impact of the reverse stock split executed in the first quarter of 2024.

Net loss for the year ended December 31, 2023, was €105.9 million, or €7.09 loss per common share compared with a net loss of €86.0 million, or €6.04 loss per common share, for the year ended December 31, 2022.

Additional information regarding these results is included in the notes to the consolidated financial statements as of December 31, 2023, included in Affimed’s filings with the U.S. Securities and Exchange Commission (SEC).

Note on International Financial Reporting Standards (IFRS)

Affimed prepares and reports consolidated financial statements and financial information in accordance with IFRS as issued by the IASB. None of the financial statements were prepared in accordance with U.S. Generally Accepted Accounting Principles. Affimed maintains its books and records in Euro.

Conference Call and Webcast Information

Affimed will host a conference call and webcast on March 28, 2024, at 8:30 a.m. EDT / 13:30 CET to discuss full year 2023 financial results and corporate developments.

The conference call will be available via phone and webcast. The live audio webcast of the call will be available in the "Webcasts" section on the "Investors" page of the Affimed website at View Source To access the call by phone, please use link:

https://register.vevent.com/register/BI43eadbb12f6143a5bdcb2c9549ef2e76, and you will be provided with dial-in details and a pin number.

Note: To avoid delays, we encourage participants to dial into the conference call 15 minutes ahead of the scheduled start time. A replay of the webcast will be accessible at the same link for 30 days following the call.

On March 28, 2024 Monopar Therapeutics Inc. (Nasdaq: MNPR), a clinical-stage biopharmaceutical company focused on developing innovative treatments for cancer patients, reported fourth quarter and full-year 2023 financial results and summarized recent developments (Press release, Monopar Therapeutics, MAR 28, 2024, View Source [SID1234641542]).

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Recent Developments

Novel MNPR-101 Radiopharmaceutical Program targeting uPAR – Phase 1 dosimetry clinical trial to commence in the coming weeks

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MNPR-101-Zr Phase 1 dosimetry clinical trial has Human Research Ethics Committee (HREC) clearance in Australia and is on track to initiate at the Melbourne Theranostic Innovation Centre (MTIC) within the next few weeks.
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Will enroll patients with advanced cancers, aiming for those most likely to have uPAR expression, which include a majority of all triple-negative breast, colorectal, and pancreatic cancers.

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Will utilize state-of-the-art positron emission tomography (PET) imaging to assess tumor uptake, normal organ biodistribution, and safety.

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Internationally recognized radiopharmaceutical physician, Professor Rodney Hicks, will be the lead investigator for the trial.

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Positive preclinical data support the potential of a MNPR-101 based radiopharmaceutical to provide a very meaningful clinical benefit to patients.

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In February 2024, Monopar shared preclinical biodistribution and efficacy data using imaging and therapeutic radioisotopes conjugated to MNPR-101. Imaging with MNPR-101-Zr in a pancreatic cancer human tumor xenograft mouse model showed high specificity and durable tumor uptake. With the therapeutic radioisotope actinium-225 (Ac-225) conjugated to MNPR-101, near complete elimination of tumor was achieved after a single injection in a triple negative breast human tumor xenograft mouse model.

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In March 2024, Monopar shared biodistribution data using the therapeutic radioisotope Lutetium-177 (Lu-177) conjugated to MNPR-101. The images show highly preferential uptake in tumor, helping explain the near complete elimination of tumors observed after a single injection of therapeutic radioisotopes bound to MNPR-101.

Camsirubicin – Phase 1b Dose-Escalation Trial, Currently enrolling the Fifth Dose-Level Cohort (650 mg/m2)

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Monopar is presently enrolling patients at the fifth dose level, which is over twice the highest dose reached in any prior camsirubicin clinical trial (650 mg/m2 versus 265 mg/m2).

Results for the Fourth Quarter and Year Ended December 31, 2023, Compared to the Fourth Quarter and Year Ended December 31, 2022

Cash and Net Loss

Cash, cash equivalents and short-term investments as of December 31, 2023, were $7.3 million. Monopar expects that its current funds, which include an additional $3.2 million from the net proceeds of its at-the-market facility in Q1 2024, will be sufficient for Monopar to continue operations at least through June 30, 2025, to conduct and conclude its first-in-human clinical trial with Monopar’s MNPR-101-Zr radiopharma program and continue the Company’s other pipeline programs.

Net loss for the fourth quarter of 2023 was $1.8 million or $0.12 per share compared to $2.9 million or $0.22 per share for the fourth quarter of 2022. Net loss for the year ended December 31, 2023 was $8.4 million or $0.61 per share compared to $10.5 million or $0.83 per share for the year ended December 31, 2022.

Research and Development (R&D) Expenses

R&D expenses for the fourth quarter of 2023 were $1.0 million compared to $2.1 million for the fourth quarter of 2022. This decrease of $1.1 million was primarily due to (1) a decrease of $0.9 million for Validive clinical trial expense, (2) a decrease of $0.2 million in camsirubicin manufacturing costs, and (3) a decrease of $0.1 million in R&D salaries, partially offset by an increase of $0.1 million in MNPR-101 radiopharmaceutical program development activities.

R&D expenses for the year ended December 31, 2023 were $5.6 million compared to $7.6 million for the year ended December 31, 2022. This decrease of $2.0 million was primarily due to (1) a decrease of $1.4 million for Validive clinical trial and manufacturing costs, (2) a decrease of $0.9 million in camsirubicin clinical trial and manufacturing costs, (3) a decrease of $0.1 million in R&D salaries, partially offset by an increase of $0.4 million in MNPR-101 radiopharma activity.

General and Administrative (G&A) Expenses

G&A expenses for the fourth quarter of 2023 were $0.9 million, compared to $0.8 million for the fourth quarter of 2022. This increase of $0.1 million was primarily due to an increase in G&A personnel expenses.

G&A expenses for the year ended December 31, 2023 were $3.2 million, compared to $2.9 million for the year ended December 31, 2022. This increase of $0.3 million was primarily due to an increase in G&A personnel expenses.

On March 28, 2024 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM:​HCM; HKEX:​13) reported that the supplemental New Drug Application ("sNDA") for savolitinib, in adult patients with locally advanced or metastatic non-small cell lung cancer ("NSCLC") with mesenchymal epithelial transition factor ("MET") exon 14 skipping alteration, has been accepted for review by the China National Medical Products Administration (NMPA) (Press release, Hutchison China MediTech, MAR 28, 2024, View Source [SID1234641497]). If approved, the new label indication for savolitinib will be expanded to include treatment-naive patients in China.

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Savolitinib was previously granted conditional approval in China for the treatment of patients with NSCLC with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. Savolitinib was launched and is marketed under the brand name ORPATHYS by our partner, AstraZeneca for this patient population, representing the first selective MET inhibitor approved in China. More than a third of the world’s lung cancer patients are in China and, among those with NSCLC globally, approximately 2-3% have tumors with MET exon 14 skipping alterations.

Preliminary efficacy and safety data from the first-line cohort of the confirmatory Phase IIIb clinical trial (NCT04923945) were presented during the IASLC World Conference on Lung Cancer (WCLC) in September 2023. Final data from the confirmatory Phase IIIb trial were presented at the European Lung Cancer Congress on March 20, 2024.

The data from this study provide confirmatory evidence for savolitinib as a targeted treatment option for treatment-naïve or previously treated patients with MET exon 14 skipping alteration NSCLC. In treatment-naïve patients, objective response rate ("ORR") was 62.1% (95% CI: 51.0% to 72.3%), disease control rate ("DCR") was 92.0% (95% CI: 84.1% to 96.7%) and median duration of response ("DoR") was 12.5 months (95% CI: 8.3 months to 15.2 months), as assessed by an independent review committee. Median progression free survival ("PFS") was 13.7 months (95% CI: 8.5 months to 16.6 months) and median overall survival ("OS") was not reached with median follow-up of 20.8 months. In previously treated patients, ORR was 39.2% (95% CI: 28.4% to 50.9%), DCR was 92.4% (95% CI: 84.2% to 97.2%) and median DoR was 11.1 months (95% CI: 6.6 months to not reached), as assessed by an independent review committee. Median PFS was 11.0 months (95% CI: 8.3 months to 16.6 months) and median OS was not mature with median follow-up of 12.5 months. Responses occurred early (time to response 1.4-1.6 months) in both treatment-naïve and previously treated patients. The safety profile was tolerable and no new safety signals were observed. The most common drug-related treatment-emergent adverse events of Grade 3 or above (5% or more of patients) were abnormal hepatic function (16.9%), increased alanine aminotransferase (14.5%), increased aspartate aminotransferase (12.0%), peripheral oedema (6.0%) and increased gamma-glutamyltransferase (6.0%).

About NSCLC and MET aberrations
Lung cancer is the leading cause of cancer death among men and women, accounting for about one-fifth of all cancer deaths.1 Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.2 The majority of NSCLC patients (approximately 75%) are diagnosed with advanced disease, and approximately 10-15% of NSCLC patients in the U.S. and Europe and 30-40% of patients in Asia have EGFRm NSCLC. 3,4,5,6

MET is a tyrosine kinase receptor that has an essential role in normal cell development.7 MET overexpression and/or amplification can lead to tumor growth and the metastatic progression of cancer cells, and is one of the mechanisms of acquired resistance to EGFR TKIs for metastatic EGFR-mutated NSCLC.7,8 Approximately 2-3% of NSCLC patients have tumors with MET exon 14 skipping alterations, a targetable mutation in the MET gene.9 Among patients who experience disease progression post-osimertinib treatment, approximately 15-50% present with MET aberration.10,11,12,13,14 The prevalence of MET depends on the sample type, detection method and assay cut-off used.15

About Savolitinib (ORPATHYS in China)
Savolitinib is an oral, potent and highly selective MET tyrosine kinase inhibitor that has demonstrated clinical activity in advanced solid tumors. It blocks atypical activation of the MET receptor tyrosine kinase pathway that occurs because of mutations (such as exon 14 skipping alterations or other point mutations), gene amplification or protein overexpression.

Savolitinib is marketed in China under the brand name ORPATHYS for the treatment of patients with non-small cell lung cancer with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. It is currently under clinical development for multiple tumor types, including lung, kidney and gastric cancers, as a single treatment and in combination with other medicines. Starting on March 1, 2023, ORPATHYS was included in the National Reimbursement Drug List (NRDL) for the treatment of locally advanced or metastatic NSCLC adult patients with MET exon 14-skipping alterations who have progressed after or unable to tolerate platinum-based chemotherapy.

In 2011, AstraZeneca and HUTCHMED entered a global licensing and collaboration agreement to jointly develop and commercialize savolitinib. Joint development of savolitinib in China is led by HUTCHMED, while AstraZeneca leads development outside of China. HUTCHMED is responsible for the marketing authorization, manufacturing and supply of savolitinib in China. AstraZeneca is responsible for the commercialization of savolitinib in China and worldwide. Sales of savolitinib are recognized by AstraZeneca.

On March 27, 2024 Transgene (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapies for the treatment of cancer, reported its financial results for 2023, and provides an update on its product pipeline and upcoming plans (Press release, Transgene, MAR 27, 2024, View Source [SID1234655850]).

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"During 2023 Transgene continued to make significant progress, delivering compelling data that confirm the value of our approach to treating cancer using our novel immunotherapies" commented Dr. Alessandro Riva, MD, Chairman and CEO of Transgene.

"At the upcoming AACR (Free AACR Whitepaper) conference in April 2024, we will be presenting additional data from the randomized Phase I study in adjuvant head and neck cancer for our lead therapeutic cancer vaccine, TG4050. Together with our partner NEC we are expanding the Phase I trial in a randomized Phase I/II to further strengthen the initial data in a larger patient population and set the foundation for a registrational development strategy."

"In the second half of 2024 we anticipate the first topline data from our fully enrolled randomized Phase II trial evaluating our shared antigens cancer vaccine TG4001 in HPV-positive anogenital cancers."

"Together with expected Phase I data from our oncolytic virus programs BT-001 and TG6050 this promises to be a key year for Transgene, with further important milestones in 2025 that we believe will enhance the value of our platform. Backed by our extended financial visibility and our strong management team we are confident in our ability to achieve our ambitious goals of delivering transformative therapies for cancer patients. I look forward to sharing updates on our continued progress."

Key events and upcoming milestones
Neoantigen therapeutic cancer vaccine (TG4050)
Additional data from the randomized Phase I trial in adjuvant head and neck cancer to be presented in H1 2024 The trial will be expanded in a randomized Phase I/II trial in the same indication. The Phase II part will start in Q2 2024.

In 2023, highly promising TG4050 data were presented at AACR (Free AACR Whitepaper) and ASCO (Free ASCO Whitepaper) 2023 (see poster here). These data show that this individualized neoantigen cancer vaccine can induce strong immune responses, which are expected to result in longer remission periods for patients.

The initial data from the randomized Phase I trial in the adjuvant treatment of head and neck cancer (NCT04183166) presented at ASCO (Free ASCO Whitepaper) showed that all evaluable patients treated with TG4050 developed a robust and specific immune response against multiple cancer neoantigens and remained disease-free. These data suggest that TG4050 can boost the immune system of patients despite a challenging tumor microenvironment at the time of tumor resection.

Transgene and its partner NEC plan to report updated data at AACR (Free AACR Whitepaper) (poster presentation on April-10, 2024) and the additional data on the 24-month median follow up of patients in H2 2024.

The randomized Phase I trial will be expanded to a randomized Phase I/II trial in the adjuvant setting of head and neck cancer. The Phase II part is expected to start enrolling patients in Q2 2024 within the framework of an extended collaboration between Transgene and NEC.

TG4050 has potential applicability across a range of solid tumors where the medical need is still significant despite the existing therapeutic option including immunotherapies. As a consequence, Transgene is performing preliminary work on a potential new Phase I trial in another undisclosed indication.

Shared antigens cancer vaccine (TG4001)
Transgene has completed the enrollment of 86 patients in the ongoing randomized Phase II trial evaluating TG4001 in HPV-positive anogenital cancers (NCT03260023). Transgene confirms that top line readouts are expected in H2 2024.

In 2023, immunological response data from TG4001 were presented in a poster at ASCO (Free ASCO Whitepaper), confirming that TG4001 can induce de novo immune responses against HPV16 antigens E6 and E7 in patients with advanced HPV16-positive anogenital cancers. Patients with a complete objective response showed strong vaccine-induced immunoreactivity.

Promising results from the previous Phase I/II trial evaluating TG4001 in combination with an immune checkpoint inhibitor were published in the September 2023 issue of the European Journal of Cancer (View Source). This study showed that TG4001 in combination with avelumab is safe and demonstrated antitumor activity in heavily pretreated HPV16-positive cancer patients. It also served as the basis for the ongoing randomized Phase II trial.

Oncolytic Viruses
In 2023, clinical data presented at AACR (Free AACR Whitepaper) confirmed the mechanism of action and the safety of our Invir.IO based oncolytic viruses, which offer a key competitive advantage with the ability to be administered intravenously. These findings support the potential of Invir.IO-based oncolytic viruses to have multiple treatment applications in a broad range of solid tumors, via intravenous, locoregional and intratumoral administration.

TG6050: Initial Phase I data expected in H2 2024, from this novel Invir.IO candidate administered intravenously
A first patient was dosed with TG6050, a novel oncolytic virus from Transgene’s Invir.IO platform, in 2023. This innovative candidate has been designed to express human IL-12, a cytokine known to trigger a potent antitumor immune response, and an anti-CTLA4 antibody. The Phase I Delivir trial (NCT05788926) is evaluating TG6050 in patients with advanced non-small cell lung cancer who have failed standard therapeutic options. Initial data from the trial is expected in H2 2024.

BT-001: Positive single agent data — Part B of the Phase I trial (combination with pembrolizumab) to deliver initial data in H2 2024
Transgene and its partner BioInvent have communicated positive data from Part A (monotherapy) of the ongoing Phase I trial in May 2023 (NCT04725331). Out of 18 patients who received escalating intratumoral doses of BT-001, two showed a decrease of injected lesion size of 50% or more, and eleven had a stabilization of the injected lesion. No safety concerns were reported.

Part B of the Phase I trial in combination with pembrolizumab (KEYTRUDA) started in October 2023. KEYTRUDA is provided by MSD (Merck & Co). Initial data from this part of the trial are expected in H2 2024.

As announced on May 5, 2023, AstraZeneca terminated its oncolytic virus research and development collaboration with Transgene following a strategic review of its pipeline.