On June 6, 2022 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical-stage targeted oncology company, reported results of a prospective analysis from the Phase 1b cohort of the KRYSTAL-1 study evaluating intracranial (IC) responses of adagrasib in patients with KRASG12C-mutated non-small cell lung cancer (NSCLC) with active and untreated central nervous system (CNS) metastases (Press release, Mirati, JUN 6, 2022, View Source [SID1234615636]). This is the first clinical data demonstrating CNS-specific activity of a KRASG12C inhibitor in patients with NSCLC with active and untreated CNS metastases. Findings show that approximately one third of the patients had an IC response in patients with CNS metastases, consistent with what was observed systemically in this cohort.

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The data will be presented today as a late-breaking oral presentation in the session titled, "Clinical Science Symposium/Including the Excluded: Advancing Care for All Patients With Lung Cancer" at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting from 5:30 to 5:42 PM ET/4:30 to 4:42 PM CT (Abstract #LBA9009).

"We are proud to share the first clinical data demonstrating CNS-specific activity of a KRASG12C inhibitor in patients with NSCLC," said Charles Baum, M.D., Ph.D., president, founder and head of research and development, Mirati Therapeutics, Inc. "Central nervous system metastases disproportionately affect patients with NSCLC and should be carefully considered as part of the treatment approach. Adagrasib showed CNS penetration and intracranial responses in patients with active and untreated CNS metastases, demonstrating potential as a treatment option for this underserved patient population."

Results of Prospective Analysis

With a median follow up of 6.6 months (data cutoff date December 2021), 25 patients with active, untreated CNS metastases were enrolled in the study and treated with adagrasib 600 mg BID.

Of the radiographically evaluable patients (n=19), results showed an IC objective response rate of 32% (6/19) by modified response assessment in neuro-oncology-brain metastases (modified RANO-BM) by blinded independent central review.

In this analysis, three patients achieved a complete response and three patients achieved a partial response. The IC disease control rate was 84% (16/19, including 10 patients with stable disease). The median IC duration of response was not reached (95% confidence interval: 4.1 – not evaluable). Concordance of disease control between systemic and IC responses was 88% (14/16). For all patients enrolled, median overall survival was not reached.

Cerebrospinal fluid (CSF) samples were obtained from two patients for whom regression of CNS metastases was observed; adagrasib CSF/free plasma concentration ratios (Kp,uu: 0.47) were consistent with other agents with known CNS penetration and activity.

The safety profile of adagrasib in this study was consistent with the overall population with no new safety signals observed. Grade 1 and 2 treatment related adverse events (TRAEs) occurred in 60% of patients. Grade 3 TRAEs occurred in 36% of patients, and there were no Grade 4/5 TRAEs.
"Central nervous system metastases occur in 27% to 42% of patients with KRASG12C-mutated NSCLC at diagnosis. These patients have a median overall survival of approximately five months, posing a serious clinical challenge," said Joshua K. Sabari, M.D., assistant professor of medicine, medical oncology at Perlmutter Cancer Center, NYU Langone Health. "With a median follow up of 6.6 months, these early and positive data show adagrasib demonstrated a meaningful overall intracranial response rate with early indications for overall survival. Adagrasib warrants further investigation on its potential to improve clinical outcomes for NSCLC patients harboring a KRASG12C-mutation who have active and untreated CNS metastases, including opportunities through Mirati’s Expanded Access Program."

Mirati also presented results from the registration-enabling Phase 2 cohort of the KRYSTAL-1 study evaluating adagrasib in patients with pre-treated NSCLC harboring a KRASG12C mutation during the Lung Cancer–Non-Small Cell Metastatic session at ASCO (Free ASCO Whitepaper) on June 3, 2022.

Virtual Investor Event

Mirati Therapeutics will host an Investor Event on Monday, June 6, 2022, at 8:00 PM ET/ 7:00 PM CT.

Company executives will provide an overview of the adagrasib clinical data presented at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting and the Company’s broader lung cancer strategy, including in earlier lines of therapy.

Investors and the general public are invited to register and listen to a live webcast of the event through the "Investors and Media" section on Mirati.com. A replay of the event will be available shortly after the conclusion of the event.

Central Nervous System (CNS) Metastases in KRAS-Mutated Lung Cancer

The brain, along with the bone, adrenals, and liver are common sites of extra-thoracic metastases in NSCLC.[1]−3 CNS metastases occur in 27−42% of patients with KRASG12C-mutated NSCLC at diagnosis.1,4−6 Additionally, patients with CNS metastases and KRAS-mutated NSCLC may have poor outcomes, with median overall survival ranging of approximately five months. 7-9

About Adagrasib (MRTX849)

Adagrasib is an investigational, highly selective, and potent oral small-molecule inhibitor of KRASG12C that is optimized to sustain target inhibition, an attribute that could be important to treat KRASG12C-mutated cancers, as the KRASG12C protein regenerates every 24–48 hours. Adagrasib is being evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including NSCLC, colorectal cancer and pancreatic cancer. For more information visit Mirati.com/science.

Mirati has an Expanded Access Program (EAP) for investigational adagrasib for the treatment of eligible patients with KRASG12C-mutated cancers, regardless of tumor type, including patients with treated or untreated CNS metastases, in the U.S. Learn more about the EAP at Mirati.com/expanded-access-policy.

On June 6, 2022 National Resilience, Inc. (Resilience), a technology-focused biomanufacturing company dedicated to broadening access to complex medicines, reported it has raised $625 million in a Series D financing, in addition to a previously unannounced $600 million Series C financing completed in August 2021 (Press release, National Resilience, JUN 6, 2022, View Source [SID1234615653]).

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The company will use the funding to continue to invest in building its infrastructure network through strategic collaborations, acquisitions, organic growth and international expansion, and by developing innovative biomanufacturing technologies to ensure the medicines of today and tomorrow can be made quickly, safely and at scale. Resilience is also investing in advanced R&D, including stable cell lines for viral vector production, distributed manufacturing for autologous cell therapy and cell-free and continuous manufacturing for biologics.

"We have an ambitious goal to reinvent biomanufacturing by bringing new processes and technologies to an industry that hasn’t kept pace with the explosive innovation in drug discovery," said Rahul Singhvi, Sc.D., Chief Executive Officer of Resilience. "While we recognize that our goal is neither quick nor easy, we are driven by our mission to democratize access to medicines. These new funds will help support our next phase of growth, as we continue to innovate biomanufacturing across all our modalities, expand our footprint to serve customers, sign strategic collaborations and support the developers of a new generation of complex medicines."

Resilience, which focuses on five therapeutic modalities – biologics, vaccines, nucleic acids and cell and gene therapies – currently has 10 facilities across North America, with more than 1 million square feet of manufacturing space and more than 1,600 employees. The company’s network, which is expected to add capacity and capabilities this year with projects underway at several existing sites, is agile enough to scale customer projects from process and analytical development through preclinical to large scale commercial drug substance and drug product manufacturing.

Resilience‘s flexible business model enables it to partner with customers of any size and across therapeutic modalities, through fee-for-service arrangements, value-share agreements and new company creation/incubation projects. The company also provides opportunities for early access and out licensing of next-generation technologies. Beyond industry customers and partners, Resilience works with government agencies, academic institutions and non-profit organizations.

The latest up-round financing was led by new and existing investors, including venture capital funds, public mutual funds, pension funds, biopharma companies, sovereign wealth funds and private family offices, among others. In total, Resilience has secured more than $2 billion in equity financing since its founding in 2020.

Recent Notable Milestones and Developments

Technology:

Acquired SwiftScale Biologics, a company developing cell-free protein synthesis, a technology that aims to eliminate the constraints of using living cells in the drug manufacturing process, resulting in faster production times, less variability across batches and greater scalability with hard-to-produce proteins.
Customers:

Established a multi-product development and manufacturing collaboration with Takeda’s Plasma-Derived Therapies Business Unit.
Secured a contract with the U.S. Department of Defense for manufacturing a monoclonal antibody as a medical countermeasure to botulinum neurotoxins.
Signed a strategic manufacturing services agreement with Opus Genetics, a gene therapy company developing treatments for inherited retinal diseases.
Manufacturing Infrastructure:

Acquired bluebird bio’s Research Triangle manufacturing facility in North Carolina.
Added capacity and capabilities including drug substance and drug product manufacturing expansions coming online in 2022 across sites in Alachua, FL, Boston and Toronto, to support biologics and vaccines.
Constructing a new, state-of-the-art facility in Marlborough, MA to support vaccines and gene therapy, coming online in 2023.
Adding a new cell and gene therapy process and analytical development as well as drug substance manufacturing site in the Philadelphia region.
Academic Collaborations & Incubations:

Launched a joint venture with The University of Texas MD Anderson Cancer Center to accelerate the development and manufacturing of innovative cell therapies for patients with cancer.
Entered into a five-year R&D alliance with Harvard University to incubate new technologies and launch companies to advance the manufacture of complex medicines.
Formed a strategic collaboration with Children’s Hospital of Philadelphia (CHOP) to implement next-generation biomanufacturing technologies and capabilities aimed at accelerating the creation of impactful therapies and technologies for the benefit of patients.
Value-Share Agreements:

Formed a strategic collaboration with Be Biopharma to manufacture engineered B Cells to create a new class of autologous and allogeneic cellular medicines.

On June 6, 2022 The Menarini Group ("Menarini") and Radius Health, Inc. ("Radius") (NASDAQ: RDUS) (collectively, the "Companies") reported the presentation at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting of data from the EMERALD phase 3 clinical trial (NCT03778931) (Press release, Menarini, JUN 6, 2022, View Source [SID1234615669]). In a non-pre-specified subgroup analysis of patients with ER+/HER2− metastatic breast cancer (mBC) without prior chemotherapy in the metastatic setting, elacestrant significantly prolonged progression-free survival (PFS) compared to standard of care (SOC) endocrine therapy.

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EMERALD study met both of its pre-specified primary end points of progression-free survival (PFS) in the overall population and in patients with ESR1 mutation (mESR1).1

77.8% (n=371) out of the 477 patients enrolled in the trial had not received prior chemotherapy in the metastatic setting for ER+/HER2−mBC. Among these patients, elacestrant showed the following results compared to SOC:
– 31% reduction in the risk of progression or death in all patients (HR=0.681 [95% CI: 0.520 – 0.891]; P=0.00388) and prolonged median PFS (3.68 vs 1.97 months).
– 46% reduction in the risk of progression or death in patients with mESR1 (HR=0.535 [95% CI: 0.356 – 0.799]; P=0.00235) and prolonged median PFS (5.32 vs 1.91 months).

At 6 months, PFS rate with elacestrant was 38.18% vs. 23.47% with SOC in the overall population, and 43.79% vs. 23.83% in the ESR1 mutation population.

PFS rate at 12 months with elacestrant was 27.12% vs. 12.19% with SOC in the overall population, and 31.48% vs. 12.36% in the ESR1 mutation population.

In exploratory subgroup analyses, elacestrant significantly reduced the risk of progression or death and prolonged median PFS vs fulvestrant in all patients without prior chemotherapy (HR=0.636 [95% CI: 0.465-0.868]; median PFS 3.68 vs 1.97 months; P=0.0032), and in patients with mESR1 without prior chemotherapy (HR=0.487 (95% CI: 0.310-0.761; median PFS 5.32 vs 1.91 months; P=0.0015).

Elacestrant had a manageable safety profile in patients without prior chemotherapy consistent with the overall population.1

Dr. Virginia Kaklamani, breast medical oncologist and professor of medicine, UT Health San Antonio, MD Anderson Cancer Center, commented, "Elacestrant is a potential exciting new endocrine therapy after progression on a CDK4/6 inhibitor in women with ER+ metastatic breast cancer. The EMERALD trial showed that elacestrant is active even in patients whose tumors harbor an ESR1 mutation. This subset analysis additionally showed that patients who have not previously been treated with chemotherapy in the metastatic setting had longer progression free survival up to 5.32 months."

Menarini plans to pursue combination studies and study the potential of elacestrant to be effective in addressing the highest unmet needs for ER+/HER2-patients.

Poster Presentation: 477

Abstract Title: Subgroup analysis of patients with no prior chemotherapy in EMERALD: A phase 3 trial evaluating elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC)

Abstract Number: 1100

Poster Session: Breast Cancer – Metastatic

About Elacestrant (RAD1901) and EMERALD Phase 3 Study

Elacestrant is an investigational selective estrogen receptor degrader (SERD), out-licensed to Menarini Group, which is being evaluated for potential use as a once daily oral treatment in patients with ER+/ HER2- advanced breast cancer. In 2018, elacestrant received fast track designation from the FDA. Preclinical studies completed prior to EMERALD indicate that the compound has the potential for use as a single agent or in combination with other therapies for the treatment of breast cancer. The EMERALD Phase 3 trial is a randomized, open label, active-controlled study evaluating elacestrant as second- or third-line monotherapy in ER+/HER2- advanced/metastatic breast cancer patients. The study enrolled 477 patients who have received prior treatment with one or two lines of endocrine therapy, including a CDK 4/6 inhibitor. Patients in the study were randomized to receive either elacestrant or the investigator’s choice of an approved hormonal agent. The primary endpoint of the study was progression-free survival (PFS) in the overall patient population and in patients with estrogen receptor 1 gene (ESR1) mutations. Secondary endpoints included evaluation of overall survival (OS), objective response rate (ORR), and duration of response (DOR).

References

1. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. J Clin Oncol. 2022 May 18:JCO2200338. doi.org: 10.1200/JCO.22.00338. Epub ahead of print.

On June 6, 2022 Seagen Inc. (Nasdaq: SGEN) and Genmab A/S (Nasdaq: GMAB) reported interim data from the innovaTV 205 trial, which included data evaluating tisotumab vedotin (TIVDAK)in combination with pembrolizumab (Cohort E) in patients with recurrent or metastatic cervical cancer (r/mCC) who have not received prior systemic therapy, with a confirmed objective response rate (ORR) of 41% (95% Confidence Interval [CI]: 24% to 59%) and median durability of response that was not reached within almost 19 months of median follow up (Press release, Seagen, JUN 6, 2022, View Source [SID1234615621]). Data were presented during an oral session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2022 Annual Meeting on June 6.

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"These data showed encouraging and durable anti-tumor activity and provide rationale for the continued development of tisotumab vedotin (TV) in front-line recurrent or metastatic cervical cancer, including its potential use as part of triplet or quadruplet combination therapy," said Domenica Lorusso, M.D., Ph.D., a gynecologic oncologist working at the Gynaecology Oncology Unit of Policlinico Gemelli IRCCS of Rome and an investigator of the innovaTV 205 clinical trial. "These early results from multiple expansion cohorts of innovaTV 205 support our continued efforts to investigate TV as part of combination therapy to further improve treatment response and durability for this group of patients with high unmet need."

Dose expansion Cohort E enrolled 33 patients with recurrent or metastatic cervical cancer who had not received any prior systemic therapy. At the time of data cutoff, the confirmed ORR among 32 evaluable patients was 41% (95% Confidence Interval [CI], range 24% to 59%), with 16% of patients (n=5) achieving complete responses and 25% of patients (n=8) achieving partial responses. Median duration of response (DOR) was not reached. Median progression-free survival (PFS) was 5.3 months (95% CI: 4.0 to 12.2).

Building on data presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021, additional longer-term follow-up data from Cohorts D (tisotumab vedotin in combination with carboplatin in previously untreated patients) and Cohort F (tisotumab vedotin in combination with pembrolizumab in previously treated patients) of the innovaTV 205 trial were also included in the ASCO (Free ASCO Whitepaper) 2022 oral presentation.

In Cohort E, the most common treatment-emergent adverse events (TEAEs) were alopecia (61%), diarrhea (55%), epistaxis (49%), conjunctivitis (45%), and nausea (46%). Prespecified adverse events (AEs) of interest (grade 1-2/grade ≥3) with tisotumab vedotin included ocular (58%/9%), peripheral neuropathy (49%/3%), and bleeding (61%/6%).

Tisotumab vedotin in combination with pembrolizumab across lines of treatment (Cohorts E/F), and with carboplatin (Cohort D) in first-line, demonstrated a tolerable and manageable safety profile. Across all three cohorts, no new safety signals were reported outside of known adverse events associated with the individual agents.

Tisotumab vedotin is approved for treatment of patients with previously treated recurrent or metastatic cervical cancer in the US and is commercialized under the tradename TIVDAK. See TIVDAK U.S. Important Safety Information, including Boxed Warning, below.

"With Genmab, we will continue to investigate tisotumab vedotin in combination with other therapies because there is still an unmet need for more effective first-line treatment for advanced cervical cancer patients," said Marjorie Green, M.D., Senior Vice President and Head of Late-Stage Development, Seagen. "We’re also researching innovative new tools to help increase awareness of the disparities and unmet needs that cervical cancer patients experience in order to better support this community in the future."

One highlight of real-world studies presented is a poster discussion on the Cervical Cancer Geographical Burden Analyzer. This is an open access, web-based, interactive tool to visualize geographical areas in the US where cervical cancer education or healthcare resource needs are high.

"The Cervical Cancer Geographical Burden Analyzer has potential to help expand understanding of cervical cancer disease burden across different communities," said Tara Castellano, M.D., Gynecologic Oncologist at Louisiana State University’s Department of Gynecologic Oncology and lead investigator for research and development of the Cervical Cancer Geographical Disease Burden Analyzer. "This tool may be particularly useful for researchers, policy makers, and advocacy groups to inform allocation of healthcare resources."

Additional updates from the tisotumab vedotin clinical development program were presented at the ASCO (Free ASCO Whitepaper) 2022 Annual Meeting, including trial-in-progress overviews for innovaTV 205/ENGOT-cx8/GOG-3024 evaluating first-line tisotumab vedotin in combination with pembrolizumab, carboplatin and bevacizumab in first-line r/mCC; and for innovaTV 207 Part D evaluating tisotumab vedotin in combination with pembrolizumab and platinum in squamous cell carcinoma of the head and neck (HNSCC) and squamous cell non-small cell lung cancer (sqNSCLC).

"The collective data presented for tisotumab vedotin at the ASCO (Free ASCO Whitepaper) 2022 Annual Meeting are reflective of our commitment to investigating this therapy across treatment lines and in combination with other therapies," said Jan van de Winkel, Ph. D., Chief Executive Officer, Genmab. "With Seagen, we are continuing to advance clinical trials in order to explore future treatment options for recurrent or metastatic cervical cancer patients."

About the innovaTV 205 Trial

The innovaTV 205 trial (also known as ENGOT-cx8/GOG-3024) is a Phase 1b/2 open-label, multi-center trial of tisotumab vedotin monotherapy and in combination with bevacizumab, pembrolizumab, or carboplatin in patients with recurrent or metastatic cervical cancer. The study consists of two parts: dose escalation (Cohorts A, B, and C) and dose expansion (Cohorts D, E, F, G and H). Patients enrolled in the dose escalation cohorts have progressed during or after standard of care therapy or are intolerant or ineligible to receive standard of care treatments. The primary objective is to identify and establish the maximum tolerated dose and Recommended Phase 2 Dose (RP2D) of tisotumab vedotin as combination therapy. Within the dose expansion cohorts, patients with recurrent or metastatic cervical cancer who have not previously received prior systemic therapy are treated in Cohorts D, E and H, with patients who have progressed on or after standard of care treatments evaluated in Cohorts F and G.For more information about the innovaTV 205 clinical trial and the study collaborators, please visit www.clinicaltrials.gov (Identifier: NCT03786081).

About Tisotumab Vedotin

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

In September 2021, the U.S. Food and Drug Administration granted accelerated approval for tisotumab vedotin-tftv (TIVDAK) in adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. TIVDAK is the first and only approved ADC for the treatment of these patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. The ongoing clinical trial innovaTV 301, an open-label, randomized, global trial, is intended as the confirmatory trial for use in verifying and describing the clinical benefit and as support for US and global regulatory applications.

Indication

TIVDAK is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information

BOXED WARNING: OCULAR TOXICITY

TIVDAK caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration. Conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care before, during, and after infusion. Withhold TIVDAK until improvement and resume, reduce the dose, or permanently discontinue, based on severity.

Warnings and Precautions

Ocular Adverse Reactions occurred in 60% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). Grade 3 ocular adverse reactions occurred in 3.8 % of patients, including severe ulcerative keratitis in 3.2% of patients. One patient experienced ulcerative keratitis with perforation requiring corneal transplantation. Cases of symblepharon were reported in patients with other tumor types treated with TIVDAK at the recommended dose. In innovaTV 204, 4% of patients experienced visual acuity changes to 20/50 or worse including 1% of patients who experienced a visual acuity change to 20/200. Of the patients who experienced decreased visual acuity to 20/50 or worse, 75% resolved, including the patient who experienced decreased visual acuity to 20/200.

Refer patients to an eye care provider for an ophthalmic exam including visual acuity and slit lamp exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care to reduce the risk of ocular adverse reactions. Promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms. Withhold dose, reduce the dose, or permanently discontinue TIVDAK based on the severity of the adverse reaction.

Peripheral Neuropathy (PN) occurred in 42% of cervical cancer patients treated with TIVDAK across clinical trials; 8% of patients experienced Grade 3 PN. PN adverse reactions included peripheral neuropathy (20%), peripheral sensory neuropathy (11%), peripheral sensorimotor neuropathy (5%), motor neuropathy (3%), muscular weakness (3%), and demyelinating peripheral polyneuropathy (1%). One patient with another tumor type treated with TIVDAK at the recommended dose developed Guillain- Barre syndrome. Monitor patients for signs and symptoms of neuropathy. For new or worsening PN, withhold, dose reduce, or permanently discontinue TIVDAK based on the severity of PN.

Hemorrhage occurred in 62% of cervical cancer patients treated with TIVDAK across clinical trials. The most common all grade hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in 5% of patients. Monitor patients for signs and symptoms of hemorrhage. For patients experiencing pulmonary or CNS hemorrhage, permanently discontinue TIVDAK. For Grade ≥2 hemorrhage in any other location, withhold until bleeding has resolved, blood hemoglobin is stable, there is no bleeding diathesis that could increase the risk of continuing therapy, and there is no anatomical or pathologic condition that can increase the risk of hemorrhage recurrence. After resolution, either resume treatment or permanently discontinue TIVDAK.

Pneumonitis: Severe, life-threatening, or fatal pneumonitis can occur in patients treated with antibody-drug conjugates containing vedotin, including TIVDAK. Among patients with cervical cancer treated with TIVDAK across clinical trials, 2 patients (1.3%) experienced pneumonitis, including 1 patient who had a fatal outcome.

Monitor patients for pulmonary symptoms of pneumonitis. Infectious, neoplastic, and other causes for symptoms should be excluded through appropriate investigations.

Withhold TIVDAK for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue TIVDAK in all patients with Grade 3 or 4 pneumonitis.

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

Adverse Reactions

In the innovaTV 204 clinical trial (n=101), serious adverse reactions occurred in 43% of patients; the most common (≥3%) were ileus (6%), hemorrhage (5%), pneumonia (4%), PN, sepsis, constipation, and pyrexia (each 3%). Fatal adverse reactions occurred in 4% of patients who received TIVDAK, including septic shock, pneumonitis, sudden death, and multisystem organ failure (each 1%).

Adverse reactions leading to permanent discontinuation occurred in 13% of patients receiving TIVDAK; the most common (≥3%) were PN (5%) and corneal adverse reactions (4%). Adverse reactions leading to dose interruption occurred in 47% of patients; the most common (≥3%) were PN (8%), conjunctival adverse reactions (4%), and hemorrhage (4%). Adverse reactions leading to dose reduction occurred in 23% of patients; the most common (≥3%) were conjunctival adverse reactions (9%) and corneal adverse reactions (8%).

The most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (52%), fatigue (50%), lymphocytes decreased (42%), nausea (41%), PN (39%), alopecia (39%), epistaxis (39%), conjunctival adverse reactions (37%), hemorrhage (32%), leukocytes decreased (30%), creatinine increased (29%), dry eye (29%), prothrombin international normalized ratio increased (26%), activated partial thromboplastin time prolonged (26%), diarrhea (25%), and rash (25%).

Drug interactions

Strong CYP3A4 Inhibitors: Concomitant use with strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the risk of TIVDAK adverse reactions. Closely monitor patients for TIVDAK adverse reactions.

Use in Specific Populations

Moderate or Severe Hepatic Impairment: MMAE exposure and adverse reactions are increased. Avoid use.

Lactation: Advise lactating women not to breastfeed during TIVDAK treatment and for at least 3 weeks after the last dose.

On June 6, 2022 Cellworks Group, Inc., a world leader in Personalized Medicine in the key therapeutic areas of Oncology and Immunology, reported results from the myCare-024-04 study, which demonstrate that the Cellworks Singula Therapy Response Index (TRI) was strongly predictive of Overall Survival (OS) and Progression-Free Survival (PFS) for newly diagnosed Glioblastoma Multiforme (GBM) patients (Press release, Cellworks, JUN 6, 2022, View Source [SID1234615654]). In this study, Singula TRI provided patient-specific estimates of OS and PFS for 18 NCCN guideline GBM therapies and provided predictive value beyond physician-prescribed therapy, patient age, patient sex, and MGMT methylation status.

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The results from the myCare-024-04 clinical study were featured in a poster presentation with comments from Dr. Manmeet Ahluwalia, M.D., M.B.A., Chief of Medical Oncology, Chief Scientific Officer and Deputy Director at Miami Cancer Institute, part of Baptist Health South Florida, at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting June 3-7th during the Central Nervous Systems Tumors Session and available online as Abstract 2053.

"The molecular heterogeneity of GBM is a key driver for the inconsistent therapy response rates that we see in brain cancer patients and makes the disease difficult to treat," said Patrick Wen, MD, Director, Center for Neuro-oncology, Dana-Farber Cancer Institute; Professor, Neurology, Harvard Medical School; and Co-Principal Investigator for the myCare-024-04 clinical study. "But by using a patient’s NGS data and Cellworks Singula to biosimulate their individual therapy responses, we can potentially improve the ability to select the most effective therapy for each GBM patient and positively effect clinical outcomes for brain cancer patients."

"The significant differences in treatment response among GBM patients necessitates moving beyond population-based treatments to personalized multi-gene therapy predictions," said Dr. Manmeet Ahluwalia, M.D., M.B.A., Chief of Medical Oncology, Chief Scientific Officer and Deputy Director at Miami Cancer Institute, part of Baptist Health South Florida; and Co-Principal Investigator for the myCare-024-04 clinical study. "Using Cellworks Singula TRI, we can simulate the molecular effects of cell signaling, drugs and radiation on patient-specific in silico diseased cells prior to treatment and then identify the magnitude of disease control and survival for specific anti-tumor strategies. The findings from using this approach in the myCare-024-04 study suggest that biosimulating guideline GBM therapies for newly diagnosed GBM patients can positively effect clinical outcomes."

The Cellworks Biosimulation Platform simulates how a patient’s personalized genomic disease model will respond to therapies prior to treatment and identifies novel drug combinations for treatment-refractory patients. The platform is powered by the groundbreaking Cellworks Computational Omics Biology Model (CBM), a network of 7,000+ human genes, 30,000+ molecular species and 100+ signaling pathways. As part of the biosimulation process, personalized disease models are created for each patient using their cytogenetic and molecular data as input to the Cellworks CBM. The Cellworks platform analyzes the impact of specific therapies on the patient’s personalized disease model and generates a Singula biosimulation report with Therapy Response Index (TRI) scores from 0 to 100 that predict the efficacy of specific chemotherapies.

myCare-024-04 Clinical Study

Background

In this study, the Cellworks Singula Therapy Response Index (TRI) was used to prospectively predict the Overall Survival (OS) and Progression-Free Survival (PFS) in a retrospective cohort of 270 IDH wildtype GBM patients from the Cancer Genome Atlas (TCGA) with known clinical outcomes treated with physician prescribed therapies. The cohort included 162 males and 108 females with a median age of 57.5 years.

Methods

A mechanistic mulit-omcis biology model created for each patient using comprehensive genomic inputs allows biosimulation of downstream molecular effects of cell signaling, drugs and radiation on a patient’s personalized in silico disease model. Stratified random sampling was used to split the data into independent training (N=153) and validation (N=117) subjects. Multivariate Cox Proportional Hazard and Proportional Odds models were used to model OS and PFS as a function of the pre-defined Singula TRI and clinical thresholds. Cox Proportional Hazards (PH) regression and likelihood ratio (LR) tests were used on the independent validation subjects to assess the hypothesis that Singula is predictive of OS and PFS above and beyond standard clinical factors.

Results

Using Cellworks Personalized Therapy Biosimulation, Singula TRI was significantly predictive of OS and PFS in univariate analyses and remained significantly predictive in multivariate analyses, which included patient age, patient sex, MGMT methylation status and drug class.

Conclusions

Cellworks Singula TRI facilitates selection of optimal personalized therapies by providing patient-specific estimates of OS and PFS for 18 NCCN guideline GBM therapies. This information may be used to estimate increases in OS and PFS when comparing Singula TRI recommended therapies verses standard care. These positive results suggest the utility of biosimulation-informed therapy selection to improve survival of GEA patients.