On December 15, 2023 Bristol Myers Squibb (NYSE: BMY) reported that the Phase 3 RELATIVITY-123 trial evaluating the fixed-dose combination of nivolumab and relatlimab for the treatment of microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients whose disease has progressed following at least one, but no more than four, prior lines of therapy for metastatic disease will be discontinued due to futility based on a planned analysis conducted by an independent data monitoring committee (Press release, Bristol-Myers Squibb, DEC 15, 2023, View Source [SID1234638613]). It was determined that the trial was unlikely to meet its primary endpoints upon completion.

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The recommendation to stop the study was not based on safety concerns. The safety profile was consistent with previously reported studies of the fixed-dose combination of nivolumab and relatlimab.

Investigation of the fixed-dose combination of nivolumab and relatlimab as a treatment for other tumor types will continue as planned. These results do not impact the currently approved indication for patients with unresectable or metastatic melanoma.

"Metastatic colorectal cancer is a challenging cancer to treat with high unmet needs. Though there have been advances in treating patients with microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) colorectal cancers, patients with microsatellite stable (MSS) tumors continue to have limited treatment options in later lines of therapy. While we know immunotherapies have historically demonstrated limited efficacy in MSS colorectal cancers, we had hoped to demonstrate meaningful clinical benefit in this patient population and are disappointed in this outcome," said Jeffrey Walch, M.D., Ph.D., vice president, global program lead, Bristol Myers Squibb. "We continue to be committed to the development of I-O therapies, including Opdivo (nivolumab) and Yervoy (ipilimumab), in MSI-H/dMMR colorectal cancers, and we thank the investigators, patients, and their loved ones who participated in this trial."

The company will share the data with investigators so they may determine appropriate next steps for patients enrolled in the RELATIVITY-123 trial. The company will complete a full evaluation of the data and work with investigators to share the results with the scientific community.

About RELATIVITY-123

RELATIVITY-123 is a Phase 3 randomized, open label, multi-center trial evaluating the fixed-dose combination of nivolumab and relatlimab compared to regorafenib or trifluridine plus tipiracil (TAS-102) in approximately 700 adult patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) whose disease has progressed following at least one but no more than four prior lines of therapy for metastatic disease. The study did not include patients with microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) tumors. The dual primary endpoints are overall survival (OS) in all randomized patients and in randomized patients with PD-L1 combined positive score (CPS) ≥ 1. Secondary endpoints include objective response rate (ORR), progression-free survival (PFS), and duration of response (DoR) by Blinded Independent Central Review per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, safety, and time until definitive deterioration-physical function and quality of life in all randomized patients and in randomized patients with PD-L1 CPS ≥ 1.

About LAG-3

Lymphocyte-activation gene 3 (LAG-3) is a cell-surface molecule expressed on effector T cells and regulatory T cells (Tregs) and functions to control T-cell response, activation and growth. LAG-3 inhibits the function of T cells when it interacts with the cell’s ligands and reduces the activation and growth of the cell on which it is found.

This T cell dysfunction allows tumors to avoid attack from the immune system and grow unchecked. Preclinical studies indicate that inhibition of LAG-3 may promote an anti-tumor response. Early research demonstrates that targeting LAG-3 in combination with other potentially complementary immune checkpoints may be a key strategy to more effectively potentiate anti-tumor immune activity.

Bristol Myers Squibb is evaluating relatlimab, its LAG-3-blocking antibody, in clinical trials in combination with other agents in a variety of tumor types.

About Colorectal Cancer

Colorectal cancer (CRC) is cancer that develops in the colon or the rectum, which are part of the body’s digestive or gastrointestinal system. Globally, CRC is the third most commonly diagnosed cancer in the world. In 2020, it is estimated that there were approximately 1,931,000 new cases of the disease and that it will be the second leading cause of cancer-related deaths among men and women combined.

Mismatch repair deficiency (dMMR) occurs when the proteins that repair mismatch errors in DNA replication are missing or non-functional, leading to microsatellite instability-high (MSI-H) tumors. Approximately 5-7% of metastatic CRC patients have dMMR or MSI-H tumors. The remaining 95% of colorectal cancer patients with microsatellite stable (MSS)/proficient mismatch repair (pMMR) tumors have limited treatment options in later-lines of therapy.

On December 15, 2023 Astellas Pharma Inc. (TSE:4503, President and CEO: Naoki Okamura, "Astellas") and Pfizer Inc. (NYSE: PFE) reported that the U.S. Food and Drug Administration (FDA) has approved PADCEV (enfortumab vedotin-ejfv, an antibody-drug conjugate [ADC]) with KEYTRUDA (pembrolizumab, a PD-1 inhibitor) for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC) (Press release, Astellas, DEC 15, 2023, View Source [SID1234638612]). This combination is the first approved to offer an alternative to platinum-containing chemotherapy, the current standard of care in first-line la/mUC.

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The approval is based on results from the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39), which demonstrated the combination nearly doubled median overall survival (OS) and median progression-free survival (PFS) in patients with previously untreated la/mUC compared to platinum-containing chemotherapy. Findings from EV-302 were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023. EV-302 also serves as the confirmatory trial for the U.S. accelerated approval of this combination for adult patients with la/mUC who are not eligible to receive cisplatin-containing chemotherapy (approved in April 2023) and expands the labeled indication to include patients who are eligible to receive cisplatin chemotherapy. EV-302 is also serving as the basis for global submissions.

Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas
"Today’s FDA approval represents a paradigm change in the treatment of advanced bladder cancer and provides hope to the thousands of Americans impacted by this aggressive disease. This achievement is notable, as it is the first regimen approved in advanced urothelial cancer that has demonstrated superiority to platinum chemotherapy, the gold standard of care for decades."

Roger Dansey, M.D., Chief Development Officer, Oncology, Pfizer
"In the Phase 3 EV-302 study, the combination of PADCEV and pembrolizumab demonstrated survival benefit for patients with advanced bladder cancer, nearly doubling median OS and median PFS compared with chemotherapy. We hope the approval of this combination will transform the standard of care for advanced bladder cancer and give patients more time with their loved ones."

The EV-302 study met its dual primary endpoints of OS and PFS compared to platinum-containing chemotherapy. Treatment with the combination resulted in a median OS of 31.5 months (95% CI: 25.4-NR) compared to 16.1 months (95% CI: 13.9-18.3) with 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 PFS 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). Consistent OS and PFS results were observed across pre-defined subgroups, including cisplatin eligibility and PD-L1 expression level. Cisplatin eligible and ineligible subgroups (n=244 and 198, respectively) saw a 47% and 57% reduced risk of death, respectively, and a 52% and 57% reduced risk of progression or death, respectively. PD-L1 and high PD-L1 expression subgroups (n=184 and 254, respectively) saw a 56% and 51% reduced risk of death, respectively, and a 50% and 58% reduced risk of progression or death, respectively.

The most common (≥20%) all-grade adverse events (AEs), including laboratory abnormalities, related to treatment with enfortumab vedotin and pembrolizumab were increased aspartate aminotransferase, increased creatinine, rash, increased glucose, peripheral neuropathy, increased lipase, decreased lymphocytes, increased alanine aminotransferase, 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. The safety results in EV-302 are consistent with those previously reported with this combination in EV-103 in cisplatin-ineligible patients with la/mUC. No new safety issues were identified.

Please see Important Safety Information at the end of this press release, including BOXED WARNING for PADCEV (enfortumab vedotin-ejfv).

Thomas Powles, M.R.C.P., M.D., Professor of Genitourinary Oncology at Queen Mary University of London; Director, Barts Cancer Center, London; EV-302 Primary Investigator
"Advanced bladder cancer is a common cause of cancer-related death. The overall survival benefit seen in the EV-302 trial demonstrates the potential for PADCEV in combination with pembrolizumab to impact first-line treatment of patients with locally advanced or metastatic urothelial carcinoma. In my opinion, this is a meaningful advancement over platinum-based chemotherapy in the systemic treatment of these patients."

Andrea Maddox-Smith, CEO, Bladder Cancer Advocacy Network (BCAN)
"Despite advances in the treatment of advanced bladder cancer, there remains a need for therapies that extend patients’ lives. Our network is thrilled that the FDA has approved a new treatment option, and we are excited about the hope it will provide to members of the bladder cancer patient community."

About EV-302
The EV-302 trial is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus 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 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 objective response rate (ORR) and duration of response (DOR) per RECIST v1.1 by BICR, and safety.

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.i
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. ii
Globally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually.iii
It is estimated that approximately 82,290 people in the U.S. will be diagnosed with bladder cancer in 2023.iv
Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra. ii
Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.v
Ongoing Investigational Trials
The EV-302 trial (NCT04223856) is an open-label, randomized, controlled Phase 3 study, evaluating the impact of treatment with enfortumab vedotin in combination with pembrolizumab versus 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 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.

About PADCEV (enfortumab vedotin-ejfv)
PADCEV (enfortumab vedotin-ejfv) is a first-in-class antibody-drug conjugate (ADC) that is directed to Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.vi Nonclinical data suggest the anticancer activity of PADCEV 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).vii

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 December 15, 2023 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that it filed regulatory application with the Ministry of Health, Labour and Welfare (MHLW) for the additional indication of an ALK inhibitor Alecensa Capsules 150 mg (Hereafter Alecensa) for Postoperative adjuvant therapy for ALK fusion gene-positive non-small cell lung cancer (Press release, Chugai, DEC 15, 2023, View Source;category= [SID1234638584]). An application for orphan drug designation has been submitted for this indication, and if designated, the review of approval for the additional indication will be subject to priority review.

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"We are pleased to have filed for additional indication of Alecensa, a Chugai original product, in Japan for the adjuvant treatment of ALK-positive NSCLC," said Chugai’s President and CEO, Dr. Osamu Okuda. "Alecensa is the first ALK inhibitor to demonstrate efficacy as an adjuvant therapy, with the potential to significantly change the patient journey in early-stage lung cancer. We remain committed to getting this drug approved for patients as quickly as possible."

The application is based on results from the ALINA study, a global Phase 3 study of Alecensa as an adjuvant therapy in patients with completely resected ALK-positive NSCLC. The study results showed that Alecensa reduces the risk of disease recurrence or death by 76% (hazard ratio [HR]=0.24, 95% CI: 0.13-0.43, p<0.0001) compared with platinum-based chemotherapy in people with completely resected stage IB (tumour ≥4cm) to IIIA ALK-positive NSCLC.1 The safety and tolerability of Alecensa in this trial were consistent with previous trials in the metastatic setting and no unexpected safety findings were observed.1

Chugai Pharmaceutical, a leading company in the oncology field, remains committed to addressing unmet medical need in cancer treatment with innovative medicines for patients and healthcare professionals.

About the ALINA study
The ALINA study [NCT03456076] is a Phase III, randomised, active-controlled, multicentre, open-label study evaluating the efficacy and safety of adjuvant Alecensa (alectinib) compared with platinum-based chemotherapy in people with completely resected stage IB (tumour ≥4cm) to IIIA (UICC/AJCC 7th edition) anaplastic lymphoma kinase (ALK)-positive NSCLC. The study includes 257 patients who were randomly assigned to either the investigational or control treatment arm. The primary endpoint is disease-free survival. Secondary outcome measures include overall survival and percentage of patients with adverse events.

About Alecensa
Alecensa is a highly selective, central nervous system-active, oral medicine created at Chugai, a member of the Roche Group, Kamakura Research Laboratories for people with non-small cell lung cancer (NSCLC) whose tumours are identified as anaplastic lymphoma kinase (ALK) positive. Alecensa is already approved in over 100 countries as an initial (first-line) and second-line treatment for ALK-positive, metastatic NSCLC, including in the United States, Europe, Japan and China. In Japan, Alecensa has also been approved for the treatment of recurrent or refractory ALK fusion gene-positive anaplastic large cell lymphoma.

About lung cancer
Lung cancer is one of the leading causes of cancer death globally.2 Each year 1.8 million people die as a result of the disease; this translates into more than 4,900 deaths worldwide every day.2 In Japan, 127 thousand people are affected by this disease (2019).3 Lung cancer can be broadly divided into two major types: non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). NSCLC is the most prevalent type, accounting for around 85% of all cases.4 Today, about half of all people with early lung cancer (45-76%, depending on disease stage) still experience a cancer recurrence following surgery, despite adjuvant chemotherapy.5 Treating lung cancer early, before it has spread, may help prevent the disease from returning and provide people with the best opportunity for a cure.6

Trademarks used or mentioned in this release are protected by law.

On December 14, 2023 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported that the U.S. Food and Drug Administration (FDA) has approved WELIREG, an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) (Press release, Merck & Co, DEC 15, 2023, View Source [SID1234638568]).

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The approval is based on statistically significant and clinically meaningful results from LITESPARK-005, which is the only trial in advanced RCC to specifically evaluate patients who have progressed following a PD-1 or PD-L1 inhibitor and a VEGF-TKI. In the trial, WELIREG demonstrated superior progression-free survival (PFS) (HR=0.75 [95% CI, 0.63-0.90]; p=0.0008) versus everolimus in advanced RCC following treatment with both a PD-1 or PD-L1 checkpoint inhibitor and a VEGF receptor targeted therapy, given in sequence or in combination. Also, WELIREG showed an objective response rate (ORR) of 22% (n=82) (95% CI, 18-27) versus 4% (n=13) (95% CI, 2-6) for everolimus.

"Despite recent progress in the treatment of advanced RCC, there is yet to be an option specifically approved for patients whose disease progresses following a PD-1 or PD-L1 inhibitor and a TKI therapy," said Dr. Toni K. Choueiri, LITESPARK-005 study chair, director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Jerome and Nancy Kohlberg professor of medicine, Harvard Medical School. "This approval of belzutifan introduces a meaningful new treatment option for certain patients, as belzutifan reduced the risk of disease progression or death compared to everolimus."

The WELIREG label contains a boxed warning that exposure to WELIREG during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of WELIREG. Advise patients of these risks and the need for effective non-hormonal contraception. WELIREG can render some hormonal contraceptives ineffective. WELIREG can cause severe anemia that can require a blood transfusion. Monitor for anemia before initiation of and periodically throughout treatment with WELIREG. WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization. Monitor oxygen saturation before initiation of and periodically throughout treatment with WELIREG. For more information, see "Selected Safety Information" below.

"In 2021, WELIREG became the first HIF-2α inhibitor therapy approved in the U.S. for the treatment of adult patients with certain VHL disease-associated tumors and is now approved for eligible patients with advanced RCC," said Dr. Marjorie Green, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories. "This approval of WELIREG marks the first new therapeutic class available for eligible patients with advanced RCC in nearly a decade, and was based on the statistically significant progression-free survival benefit observed in patients following treatment with a PD-1 or PD-L1 inhibitor and a VEGF-TKI when compared to everolimus."

Study design and additional data supporting the approval

The approval was based on data from LITESPARK-005, an open-label, randomized, active-controlled clinical trial (ClinicalTrials.gov, NCT04195750) in 746 patients with unresectable, locally advanced or metastatic clear cell RCC that progressed following PD-1 or PD-L1 checkpoint inhibitor and VEGF receptor targeted therapies either in sequence or in combination. Patients could have received up to three prior treatment regimens and were required to have measurable disease per RECIST v1.1. Patients were randomized 1:1 to receive WELIREG (120 mg) (n=374) or everolimus (10 mg) (n=372) orally once daily. Randomization was stratified by the International Metastatic RCC Database Consortium (IMDC) risk categories (favorable versus intermediate versus poor) and the number of prior VEGF receptor targeted therapies (1 versus 2-3). Patients were evaluated radiologically at Week 9 from the date of randomization, then every 8 weeks through Week 49, and every 12 weeks thereafter.

The major efficacy endpoints were PFS as assessed by blinded independent central review (BICR) according to RECIST v1.1 and overall survival. Additional efficacy endpoints included ORR as assessed by BICR according to RECIST v1.1.

The trial demonstrated a statistically significant improvement in PFS for patients randomized to WELIREG compared with everolimus.

Among the 82 patients treated with WELIREG who achieved a confirmed response based on BICR per RECIST 1.1, 25 (30%) patients had a duration of response ≥12 months. Overall survival results were immature. At the time of the subsequent pre-specified analysis, 59% of the patients had died in the randomized population.

In the trial, WELIREG reduced the risk of disease progression or death by 25% (HR=0.75 [95% CI, 0.63-0.90]; p=0.0008) versus everolimus in these patients. Median PFS was 5.6 months (95% CI, 3.9-7.0) for WELIREG versus 5.6 months (95% CI, 4.8-5.8) for everolimus. The ORR for WELIREG was 22% (n=82) (95% CI, 18-27), with a complete response (CR) rate of 3% (n=10) and a partial response (PR) rate of 19% (n=72), and the ORR for everolimus was 4% (n=13) (95% CI, 2-6), with no patients achieving a CR and a PR rate of 4% (n=13).

The median duration of exposure was 7.6 months (range, 0.1 to 28.5 months) for WELIREG. Serious adverse reactions occurred in 38% of patients who received WELIREG. Serious adverse reactions in ≥2% of patients who received WELIREG were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%) and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received WELIREG, including sepsis and hemorrhage (0.5% each). Permanent discontinuation of WELIREG due to adverse reactions occurred in 6% of patients. Adverse reactions that resulted in permanent discontinuation of WELIREG (≥0.5%) were hypoxia (1.1%), anemia and hemorrhage (0.5% each). Dosage interruptions of WELIREG due to an adverse reaction occurred in 39% of patients. Adverse reactions that required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%) and hemorrhage (2.2%). Dose reductions of WELIREG due to an adverse reaction occurred in 13% of patients. Adverse reactions that required dose reduction in ≥1% of patients were hypoxia (5%) and anemia (3.2%). The most common (≥25%) adverse reactions, including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin, fatigue, musculoskeletal pain, increased creatinine, decreased lymphocytes, increased alanine aminotransferase, decreased sodium, increased potassium, and increased aspartate aminotransferase. Clinically relevant adverse reactions in <10% of patients who received WELIREG in LITESPARK-005 included hemorrhage (9%) [including intracranial/cerebral hemorrhage (0.8%)], rash (8%), hypertension (6%), visual impairment [including vision blurred (4%), visual acuity decreased (1.1%), visual impairment (0.5%), and retinal detachment (0.3%)] (6%), and increased weight (5%).

About renal cell carcinoma

Renal cell carcinoma is by far the most common type of kidney cancer; about 9 out of 10 kidney cancer diagnoses are RCCs. Renal cell carcinoma is about twice as common in men than in women. Most cases of RCC are discovered incidentally during imaging tests for other abdominal diseases. Approximately 15% of patients with kidney cancer are diagnosed at an advanced stage.

About WELIREG (belzutifan) 40 mg tablets, for oral use

Indications in the U.S.

Certain von Hippel-Lindau (VHL) disease-associated tumors

WELIREG (belzutifan) is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.

Advanced Renal Cell Carcinoma (RCC)

WELIREG is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI).

Selected Safety Information for WELIREG

Warning: Embryo-Fetal Toxicity

Exposure to WELIREG during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of WELIREG. Advise patients of these risks and the need for effective non-hormonal contraception as WELIREG can render some hormonal contraceptives ineffective.

Anemia

WELIREG can cause severe anemia that can require blood transfusion. Monitor for anemia before initiation of, and periodically throughout, treatment. Transfuse patients as clinically indicated. For patients with hemoglobin <8 g/dL, withhold WELIREG until ≥8 g/dL, then resume at the same or reduced dose or permanently discontinue WELIREG, depending on the severity of anemia. For life-threatening anemia or when urgent intervention is indicated, withhold WELIREG until hemoglobin ≥8 g/dL, then resume at a reduced dose or permanently discontinue WELIREG.

In LITESPARK-004 (N=61), decreased hemoglobin occurred in 93% of patients with VHL disease and 7% had Grade 3 events. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months).

The use of erythropoiesis-stimulating agents (ESAs) for treatment of anemia is not recommended in patients with VHL disease who are treated with WELIREG.

In LITESPARK-005 (n=372), decreased hemoglobin occurred in 88% of patients with advanced RCC and 29% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 16.6 months). Of the patients with anemia, 22% received transfusions only, 20% received ESAs only, and 12% received both transfusion and ESAs.

Hypoxia

WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization.

Monitor oxygen saturation before initiation of, and periodically throughout, treatment. For decreased oxygen saturation with exercise (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same or a reduced dose. For decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg) or when urgent intervention is indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening or recurrent symptomatic hypoxia, permanently discontinue WELIREG. Advise patients to report signs and symptoms of hypoxia immediately to a healthcare provider.

In LITESPARK-004, hypoxia occurred in 1.6% of patients.

In LITESPARK-005, hypoxia occurred in 15% of patients and 10% had Grade 3 events. Of the patients with hypoxia, 69% were treated with oxygen therapy. Median time to onset of hypoxia was 30.5 days (range: 1 day to 21.1 months).

Embryo-Fetal Toxicity

Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman.

Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. WELIREG can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.

Adverse Reactions

In LITESPARK-004, serious adverse reactions occurred in 15% of patients, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each).

WELIREG was permanently discontinued due to adverse reactions in 3.3% of patients for dizziness and opioid overdose (1.6% each).

Dosage interruptions due to an adverse reaction occurred in 39% of patients. Those which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness.

Dose reductions due to an adverse reaction occurred in 13% of patients. The most frequently reported adverse reaction which required dose reduction was fatigue (7%).

The most common adverse reactions (≥25%), including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin (93%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%).

In LITESPARK-005, serious adverse reactions occurred in 38% of patients. The most frequently reported serious adverse reactions were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%), and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received WELIREG, including sepsis (0.5%) and hemorrhage (0.5%).

WELIREG was permanently discontinued due to adverse reactions in 6% of patients. Adverse reactions which resulted in permanent discontinuation (≥0.5%) were hypoxia (1.1%) and hemorrhage (0.5%).

Dosage interruptions due to an adverse reaction occurred in 39% of patients. Adverse reactions which required dosage interruption in 2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%), and hemorrhage (2.2%).

Dose reductions due to an adverse reaction occurred in 13% of patients. The most frequently reported adverse reactions which required dose reduction (≥1.0%) were hypoxia (5%) and anemia (3.2%).

The most common (≥25%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (88%), fatigue (43%), musculoskeletal pain (33%), increased creatinine (34%), decreased lymphocytes (34%), increased alanine aminotransferase (32%), decreased sodium (31%), increased potassium (29%), and increased aspartate aminotransferase (27%).

Drug Interactions

Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan, which may increase the incidence and severity of adverse reactions. Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended.

Coadministration of WELIREG with CYP3A4 substrates decreases concentrations of CYP3A4 substrates, which may reduce the efficacy of these substrates or lead to therapeutic failures. Avoid coadministration with sensitive CYP3A4 substrates. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information. Coadministration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding.

Lactation

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with WELIREG and for 1 week after the last dose.

Females and Males of Reproductive Potential

WELIREG can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating treatment with WELIREG.

Use of WELIREG may reduce the efficacy of hormonal contraceptives. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.

Based on findings in animals, WELIREG may impair fertility in males and females of reproductive potential and the reversibility of this effect is unknown.

Pediatric Use

Safety and effectiveness of WELIREG in pediatric patients under 18 years of age have not been established.

On December 14, 2023 Morphogenesis, Inc. ("Morphogenesis"), a Phase 3 registration-stage immuno-oncology company developing novel technologies to overcome resistance to cancer immunotherapy, reported its corporate rebranding and provided a business overview. Effective immediately, the company will operate under the name TuHURA Biosciences, Inc. ("TuHURA") (Press release, Morphogenesis, DEC 14, 2023, View Source [SID1234643367]).

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"We are very pleased to announce our corporate rebranding which now clearly aligns with our development focus and emphasizes our commitment to overcoming the major obstacles that limit the effectiveness of cancer immunotherapies," commented James Bianco, M.D., President and Chief Executive Officer of TuHURA. "Our technology platforms have the potential to significantly increase the number of cancer patients that can respond to immunotherapies, such as checkpoint inhibitors. Looking ahead, we are driving our lead clinical program, IFx-2.0 personalized cancer vaccine, forward and are on track initiate our single Phase 3 registration study in 2024."

TuHURA’s Strategy

TuHURA’s strategy is to leverage its technologies and novel product candidates as adjunctive therapy to overcome primary and acquired resistance to checkpoint inhibitors, molecularly modified immune therapies and cellular therapies. The key elements of this strategy include:

Shortening the time and cost to product registration;
Establishing a leadership position in developing first-in-class bi-functional ADCs;
Expanding the application of its IFx-2.0 personalized cancer vaccine;
Leveraging the IFx technology platform to develop next generation candidates to expand into blood related cancers; and
Establishing development and commercial license collaborations.
TuHURA’s Focus

The company is focused on advancing its two innovative platform technologies:

IMMUNE FX (IFx): Personalized Cancer Vaccines Harnessing the Power of the Innate Immune Response

TuHURA’s IFx technology utilizes a proprietary plasmid DNA ("pDNA") or messenger RNA ("mRNA") which, when introduced into a tumor cell, results in the expression of a highly immunogenic bacterial protein (emm55) from a rare variant of Streptococcus pyogenes on the surface of the tumor cell.

The company’s lead program, IFx-2.0, is designed to harness the power of the patient’s innate immune response, which has evolved over time to be conserved to detect foreign pathogens like bacterial proteins. By making the surface of a tumor look like a bacterium, IFx-2.0 is designed to use the tumor itself as the source of foreign neoantigens to prime and initiate an innate immune response against the tumor restoring the cancer immunity cycle leading to adaptive immune response.

Program Highlights:

IFx-2.0 makes patient’s entire tumor appear foreign activating the innate immune response allowing checkpoint inhibitors to work where they previously failed or where they normally would not work.
Produced high rates of durable systemic objective responses across multiple cutaneous malignancies including in advanced or metastatic Merkel Cell Carcinoma (MCC), cutaneous Squamous Cell Carcinoma and Melanoma that exhibited primary resistance to checkpoint inhibitor therapy in Phase 1 and Phase 1b clinical trials.
Demonstrated excellent safety profile when used as adjunctive therapy with a checkpoint inhibitor.
Preparing to commence single Phase 3 registration directed pivotal trial to be conducted under Accelerated Approval pathway for first line treatment of advanced or metastatic MCC when used as adjunctive therapy with pembrolizumab.
Bi-Functional Antibody Drug Conjugates (ADCs): Targeting Myeloid Derived Suppressor Cells (MDSCs) to Modulate Their Immunosuppressive Effects on the Tumor Microenvironment

Leveraging its proprietary Delta receptor technology TuHURA is developing first-in-class bi-functional ADCs that target MDSCs: cells which are responsible for creating an immunologic sanctuary through their immunosuppressing effects on the tumor microenvironment (TME). The TME is the tissue surrounding a tumor; MDSCs are a heterogeneous group of immature myeloid cells that are characterized by the ability to suppress both innate and adaptive immune responses. MDSCs are generally believed to be responsible for T cell exhaustion and acquired resistance to checkpoint inhibitors and cellular therapies. Utilizing its ADCs to inhibit the immune suppressing effects of MDSCs, while localizing an immune checkpoint inhibitor or T cell activator in the TME, TuHURA believes it may be able to prevent T cell exhaustion and acquired resistance to checkpoint inhibitors and cellular therapies, allowing them to continue working.

Program Highlights:

First to identify the presence of a novel Delta receptor present in high quantities on the surface of tumor associated MDSCs.
Delta receptor represents a "master switch" controlling multiple MDSC pathways responsible for creating immune sanctuary where tumor lives.
Developing Delta specific and selective small molecule inhibitors as core for company’s bi-functional ADCs.
Unlike conventional ADCs, TuHURA’s bi-functional ADCs target and inhibit Delta receptor on MDSCs removing their immune suppressing effects while localizing an immune effector like a checkpoint inhibitor where the tumor lives.
Additionally, the company is advancing IFx-3.0, a personalized cancer vaccine to be delivered intravenously, which leverages the clinical validation of the IFx-2.0 clinical program. IFx-3.0 utilizes the company’s proprietary emm55 mRNA to target CD22, which is overexpressed on cancerous B-cells. TuHURA expects to begin IND enabling studies in the second half of 2024.

Program Highlights:

Developed proprietary CD22 targeting antibody fragment (scFv) coupled to mRNA loaded lipid nanoparticle.
CD22 overexpressed on malignant B cells allowing IFx-3.0 mRNA payload to be selectively targeted to and expressed in cancerous B cells.
Expands cancer vaccine technology to blood related cancers.
For more information about the company’s innovative platform technologies and development programs, please visit tuhurabio.com.