On June 5, 2022 Agendia, Inc., a commercial-stage company focused on improving outcomes for breast cancer patients worldwide by providing physicians and patients with next-generation diagnostic and information solutions to inform optimized treatment decision-making, reported it will present seven posters derived from the company’s FLEX Trial, the real-world, multicenter, prospective, observational breast cancer study at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (ASCO) (Free ASCO Whitepaper) 2022 (Press release, Agendia, JUN 5, 2022, View Source [SID1234615578]).

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One of Agendia’s posters, selected for the oral discussion session, titled Whole transcriptomic analysis of HR+ breast cancer in Black women classified as basal-type by BluePrint [Reid, S., et al.], will present findings from a racially-diverse cohort and resulting transcriptomic analyses suggesting hormone receptor-positive (HR+)/Basal tumors are biologically similar to triple-negative breast cancer (TNBC) tumors, regardless of race, demonstrating the importance of subtyping a tumor’s biology to determine optimal treatment course. BluePrint also identified racial disparities in the proportion of HR+/Basal tumors, showing a near doubling of such tumors among Black women, underscoring the need for diverse representation in clinical trials, a hallmark of the FLEX Trial.

"Leveraging the BluePrint assay, we are able to uncover new gene expression insights for HR+/Basal breast cancer tumors, which traditionally are more aggressive, higher grade, and disproportionally impact Black women compared to White women," said Sonya Reid, MD, MPH, Department of Medicine, Vanderbilt University Medical Center. "The FLEX Trial’s robust collection of diverse patient genomic profiles uniquely allows for sub-studies analyses like these to take place, helping researchers better support their patients from all racial and ethnic backgrounds with further classification of breast cancer tumors."

These data build on findings presented at San Antonio Breast Cancer Symposium 2021, also authored by Dr. Reid, that showed MammaPrint and BluePrint more robustly identify differences in more aggressive breast cancers in Black and White women beyond clinical factors, highlighting the fundamental importance of genomic classification and personalized treatment planning.

In addition, Agendia will present several sub-studies highlighting the FLEX Trial’s approach to cancer research by accelerating impactful data generation, aimed at redefining cancer care. The company believes this patient-centric design and national network of participating sites backed by Agendia will allow its investigator-initiated sub-studies to produce important results with the potential to drive science forward, like those being shared at ASCO (Free ASCO Whitepaper) 2022:

Clinical implications for patients with discordant Oncotype and MammaPrint results [Socoteanu, M., et al.] recalls findings from the IMPACT trial, which demonstrated MammaPrint and BluePrint inform treatment planning and increase physician confidence. In an effort to examine consistency among genomic tests, researchers analyzed therapy implications for patients who received both results from MammaPrint and BluePrint as well as OncotypeDx within the FLEX Trial:
Of 722 patients, 49% were observed to have discordant results with the potential of negative clinical impact. This includes 27% who may be undertreated, 6% potentially overtreated, and 10% who may not be given the option to decrease endocrine therapy to two years based on MammaPrint Ultra Low genomic risk assessment. Of 114 concordant MammaPrint High Risk tumors, 14% were genomically classified as Basal, and likely require more aggressive chemo than typically used in estrogen receptor-positive (ER+) breast cancers.
Together, these analyses showed more than half the patients in this cohort were at potential risk for undertreatment or overtreatment, had they received an OncotypeDx test as a standalone test. Discordance between OncotypeDx Recurrence Scores and MammaPrint with BluePrint results, most often yields the potential for undertreatment if the Recurrence Score is relied upon for treatment decision-making, putting a significant amount of risk on the patient since undertreatment may result in an incurable metastatic recurrence.
Whole transcriptome analysis of tumors with discordant Oncotype and MammaPrint results in the FLEX trial [Socoteanu, M., et al.] also looked at the differences in quality of results from OncotypeDx Recurrence Scores in comparison to MammaPrint results, this time by evaluating the genomic diversity within each test’s classification. The analysis found a high amount of genomic diversity within the OncotypeDx Recurrence Score Intermediate group, while conversely showing MammaPrint further classifies cases into more genomically rich and distinct categories, allowing for more precise treatment pathways based on the individual tumor.
Investigation of a genomic signature for transcription factor MAF gene amplification and lack of bisphosphonate benefit in early breast cancer [Nasrazadani, A. et al.] provides whole transcriptome analyses suggesting breast cancer tumors with mesenchymal aponeurotic fibrosarcoma (MAF) gene amplifications – a biomarker associated with shortened survival and lack of bisphosphate benefit when related to bone metastases in breast cancer – may be identified by a unique gene expression pattern. In this study, researchers used the MammaPrint/BluePrint platform to identify a set of 57 genes that could potentially predict MAF amplification status which could enable a woman’s care team to potentially anticipate a lack of benefit from adjuvant bisphosphonate treatment. Additionally, these results show mining the complete genome more thoroughly provides expanded insights and can shed light on new biomarkers previously unknown.
Distribution of breast cancer molecular subtypes within receptor classifications: Lessons from the I-SPY2 trial and FLEX Registry [Cha, J., et al.] proposes that the breast cancer research community drive science forward and work with the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program to update its immunohistochemical (IHC) labels to avoid overlap with molecular subtype nomenclature and incorporate more modern classifications when available. Study results show the SEER Program database using IHC labels is not accurately identifying genomic subtypes via its annotations. In fact, the categorizations in the population-based registry were discordant with MammaPrint and BluePrint results in 52% of I-SPY2 Trial cases and 43% of FLEX Trial cases, emphasizing the growing importance of molecular subtyping to inform treatment and epidemiological research.
Defining transcriptomic profiles of early-stage mucinous breast cancers: A FLEX sub study [Sivapiragasam, A., et al.] revealed although mucinous breast cancer (MuBC), a rare subtype of invasive ductal carcinoma (IDC) accounts for less than 2% of all breast cancers, it often is expected to have low clinical risk and a favorable prognosis, however new genomic testing showed half of the patients observed in the study were in fact classified as MammaPrint High Risk. Through the examination of transcriptomic profiles, the findings demonstrated MammaPrint Low Risk MuBC is biologically different from MammaPrint Low Risk IDC providing new evidence as to why there are more favorable prognoses. Results also indicated MammaPrint High Risk MuBC and High Risk IDCs are highly genomically similar and could benefit from chemotherapy, providing additional clarity to guide specific treatment among these breast cancer subtypes.
FLEX, the 30,000 breast cancer transcriptome project: A platform for early breast cancer research using full-genome arrays paired with clinical data [Ma, C., et al.] shares data from the 38 investigator-initiated sub-studies – including five investigating racial disparities – approved within the FLEX Real World Evidence Trial (NCT03053193). Since the trial’s inception in 2017, FLEX has enrolled 10,000 patients at over 109 sites with a diverse data set designed to meet the needs of historically under-represented patients with breast cancer.
"These new findings presented at ASCO (Free ASCO Whitepaper) 2022 show the breadth of the FLEX research platform to identify and evaluate the many different complexities of a breast cancer biology at diagnosis that may facilitate more precise and individualized treatment recommendations," said William Audeh, MD, Chief Medical Officer at Agendia. "Agendia’s commitment to expanding our understanding of breast cancer to improve outcomes for women with breast cancer is astounding, exemplified by the FLEX Real World Evidence Trial. FLEX has the significant potential to broaden the application of genomic information through assays such as MammaPrint, BluePrint, and new proprietary Agendia signatures, which could lead to practice-changing models within breast cancer care aimed at improved outcomes for women with breast cancer."

On June 5, 2022 Eisai reported new investigational data from the platinum-resistant ovarian cancer (PROC) cohort expansion of a Phase 1 study (Study 101) evaluating the antibody drug conjugate (ADC) co-developed by Eisai and Bristol Myers Squibb, farletuzumab ecteribulin (MORAb-202) (Press release, Eisai, JUN 5, 2022, View Source [SID1234615595]). The safety and efficacy findings are being featured in a poster discussion at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (#ASCO22), a hybrid meeting in Chicago from June 3 to 7 (NCT03386942; Abstract: #5513). Farletuzumab ecteribulin is composed of Eisai’s in-house developed farletuzumab, a humanized IgG1 monoclonal antibody that binds to the folate receptor alpha (FRα), and Eisai’s anticancer agent eribulin, a microtubule dynamics inhibitor, using an enzymatically cleavable linker.

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"We are encouraged by the clinical safety and efficacy results, as measured by the preliminary antitumor activity observed in patients with platinum-resistant ovarian cancer being treated with each dose of farletuzumab ecteribulin, and with varying levels of folate receptor alpha expression," said Shin Nishio, MD, PhD, Principal Investigator and Associate Professor, Department of Obstetrics and Gynecology, Kurume University School of Medicine, Fukuoka, Japan. "Based on the data from pre-clinical studies, farletuzumab ecteribulin has the clinical potential to elicit a bystander effect through an enzymatically cleavable linker that releases a toxic payload from the antibody, therefore acting not only on the folate receptor alpha-positive cancer cells, but also the folate receptor alpha-negative cancer cells surrounding the folate receptor alpha-positive cancer cells. As the field of targeted therapy continues to evolve, antibody drug conjugates are anticipated to become a key modality in the treatment of recurrent, platinum-resistant disease."

Ovarian cancer is typically diagnosed at advanced stages of disease, with most patients facing a poor prognosis because of high rates of recurrence and subsequent development of chemoresistance.1 High-grade serous ovarian cancer (HGSOC) is the most common type of ovarian cancer and tends to spread before it can be detected.2-3 Ovarian tumors express a great number of tumor-antigens that can be used to guide targeted medicines, including the FRα biomarker, which is often overexpressed in epithelial ovarian carcinomas.4-5 FRα is considered as a marker of tumor aggressiveness and is associated with poorer response rates to treatment.6

"As part of our human health care mission, Eisai remains dedicated to exploring novel treatment approaches with the goal of addressing unmet needs of people living with cancer," said Dr. Takashi Owa, President, Oncology Business Group at Eisai. "The data for our first antibody drug conjugate, which was discovered in-house with Eisai technology, demonstrate the company’s commitment to working to advance precision medicine to improve care for women in need of additional treatment options. We look forward to sharing further results assessing farletuzumab ecteribulin as a potential treatment for patients with platinum-resistant ovarian cancer."

Trial Design
The primary objective of this Phase 1 study conducted in Japan (Study 101) was to determine the safety and tolerability of farletuzumab ecteribulin. Selected secondary objectives included determining the recommended dose of farletuzumab ecteribulin for future studies, pharmacokinetic characterization and an efficacy assessment, including objective response rate (ORR) and disease control rate (DCR). Doses of farletuzumab ecteribulin from 0.3 to 1.2 mg/kg, administered by intravenous (IV) fusion every 3 weeks (Q3W), were then evaluated. The dose-escalation part of Study 101 suggested that treatment with farletuzumab ecteribulin led to antitumor activity in patients with FRα-positive solid tumors, including patients with ovarian cancer. Based on the efficacy and safety results from the dose-escalation part of this study, farletuzumab ecteribulin 0.9 mg/kg (Cohort 1) and 1.2 mg/kg (Cohort 2) administered by IV fusion Q3W were selected for the expansion part of this study in patients with platinum-resistant ovarian cancer. Patients were required to have FRα-positive tumors, assessed by immunohistochemistry assay, with positive expression defined as > 5% of cells stained on a slide at 1+, 2+ or 3+ intensity level. In the expansion phase of this study, tumor assessments were performed based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) at baseline and every 6 weeks until week 36, thereafter every 8 weeks, and at treatment discontinuation (or as clinically indicated). Complete and partial responses required confirmation of the next response at ≥ 4 weeks. Interstitial lung disease (ILD)/pneumonitis assessment in 0.9 mg/kg dose group was performed by external ILD experts committee before moving to 1.2 mg/kg dose group. In the case of ILD/pneumonitis, dosing of farletuzumab ecteribulin could be modified, interrupted or permanently discontinued depending on the severity. Other management options for ILD/pneumonitis included pulmonology consult, radiographic imaging, monitoring for signs and symptoms, prednisolone administration, or treatment according to local practice guidelines.

Safety and Efficacy Results
Interstitial lung disease/pneumonitis was the most common treatment-emergent adverse event (TEAE) (Cohort 1: 37.5%; Cohort 2: 66.7%) and was of low-grade severity in most patients in Cohort 1 (Grade 1: 33.3%; Grade 2: 4.2%; Grades 3-5: 0) and Cohort 2 (Grade 1: 28.6%; Grade 2: 33.3%; Grade 3: 4.8%; Grades 4-5: 0). The next most common TEAEs of any grade after ILD were pyrexia (Cohort 1: 33.3%; Cohort 2: 42.9%), headache (Cohort 1: 12.5%; Cohort 2: 47.6%) and nausea (Cohort 1: 25.0%; Cohort 2: 33.3%). Grade ≥3 TEAEs occurred in 33.3% of patients in Cohort 1 and 28.6% of patients in Cohort 2.

Treatment with farletuzumab ecteribulin resulted in an ORR of 25.0% (6 patients) in Cohort 1 (n=24) and 52.4% (11 patients) in Cohort 2 (n=21). In patients with HGSOC, ORR was 31.6% (6 out of 19 patients) in Cohort 1 and 50.0% (10 out of 20 patients) in Cohort 2. For patients with FRα-expression levels of less than 50.0%, treatment with farletuzumab ecteribulin led to an ORR of 33.3% (2 out of 6 patients) in Cohort 1 and 50.0% (1 out of 2 patients) in Cohort 2. For patients with FRα-expression levels of greater than or equal to 50.0%, treatment with farletuzumab ecteribulin led to an ORR of 22.2% (4 out of 18 patients) in Cohort 1 and 52.6% (10 out of 19 patients) in Cohort 2 (Table 1).

Table 1. Tumor Responses as Assessed by Investigator per RECIST v1.1

Parameter

Cohort 1

farletuzumab ecteribulin 0.9 mg/kg

n=24

Cohort 2

farletuzumab ecteribulin 1.2 mg/kg

n=21

CR, n (%)

1 (4.2)

0

PR, n (%)

5 (20.8)

11 (52.4)

SD, n (%)

10 (41.7)

9 (42.9)

PD, n (%)

8 (33.3)

1 (4.8)

ORR, n (%), (95% CI)

6 (25.0), (9.8–46.7)

11 (52.4), (29.8–74.3)

ORR by FRα status,

n of n (%), (95% CI)

FRα < 50%

FRα ≥ 50%

2 of 6 (33.3), (4.3-77.7)

4 of 18 (22.2), (6.4-47.6)

1 of 2 (50.0), (1.3-98.7)

10 of 19 (52.6), (28.9-75.6)

ORR by HGSOC status,

n of n (%), (95% CI)

HGSOC

Non-HGSOC

6 of 19 (31.6), (12.6-56.6)

0 of 5, (0)

10 of 20 (50.0), (27.2-72.8)

1 of 1 (100), (2.5-100)

DCR, n (%), (95% CI)

16 (66.7), (44.7–84.4)

20 (95.2), (76.2–99.9)

Median DOR, months (95% CI)

10.6 (3.9-NE)

7.6 (4.3-10.8)

Data cutoff date: October 31, 2021.

CI, confidence interval; CR, complete response; ORR, objective response rate (CR+PR); DCR, disease control rate (CR+PR+SD [≥ 5 weeks]); DOR, duration of response; FRα, folate receptor alpha; HGS, high-grade serous; NE, not estimable; PD, progressive disease; PR, partial response; RECIST v1.1; Response Evaluation Criteria in Solid Tumors; SD, stable disease.

Poster Presentation Featuring Analyses Based on PK/PD Modeling/Simulations for Dose Optimization of Farletuzumab Ecteribulin Including Findings for Body Surface Area-Based Dosing (Abstract: #3090)

Eisai presented a poster featuring analyses from Study 101 based on PK/PD modeling/simulations for dose optimization of farletuzumab ecteribulin at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting. Based on the results of these simulations, body surface area-based (BSA) dosing is predicted to lower the exposure-dependent ILD risk in patients with higher body weight while maintaining clinical efficacy, compared to body weight-based dosing. BSA-based dosing is common with ADC therapies. Optimization of body surface area-based dosing is ongoing to evaluate the potential benefits and risks of treatment with farletuzumab ecteribulin in a Phase 1/2 clinical study (NCT04300556; Study 201) in the United States.

About Farletuzumab Ecteribulin (MORAb-202)
Farletuzumab ecteribulin is Eisai’s first antibody drug conjugate (ADC) that is composed of Eisai’s in-house developed farletuzumab, a humanized IgG1 monoclonal antibody that binds to the folate receptor alpha (FRα), and Eisai’s in-house developed anticancer agent eribulin, using an enzymatically cleavable linker. Eisai has entered into an exclusive global strategic collaboration agreement with Bristol Myers Squibb for the co-development and co-commercialization of farletuzumab ecteribulin. Eisai is currently conducting a Phase 1 clinical study in Japan (NCT03386942) and a Phase 1/2 clinical study in the United States (NCT04300556), respectively, for farletuzumab ecteribulin targeting FRα-positive solid tumors. Other studies are in development by Eisai and Bristol Myers Squibb. After farletuzumab ecteribulin enters the target FRα-positive cancer cells, it is thought that the linker is enzymatically cleaved, releasing eribulin from the antibody leading to its antitumor activity. When the anticancer agent and antibody components of an ADC are separated inside a targeted antigen-positive cancer cell, it is theorized that the released anticancer agent also has a bystander effect on neighboring antigen-negative cancer cells and the component cells of the tumor microenvironment. In pre-clinical studies, farletuzumab ecteribulin demonstrated a bystander effect, with antitumor activity on the FRα-negative cancer cells surrounding the FRα-positive cancer cells.

The payload eribulin was the first in the halichondrin class of microtubule dynamics inhibitors. Structurally, eribulin is a simplified and synthetically produced version of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai, and functions by inhibiting the growth phase of microtubule dynamics which prevents cell division.

About Ovarian Cancer
Ovarian cancer begins in the ovary or related areas of the fallopian tube or peritoneum, and is characterized by uncontrolled growth of cells in these areas.7 It is the eighth most commonly diagnosed cancer in women worldwide.8 In 2022, nearly 20,000 new cases of ovarian cancer will be diagnosed in the U.S. and about 13,000 women will die from the disease.2 About 90% of cases are epithelial ovarian cancer, the majority of which are high-grade serous tumors (HGSOC), which have the fewest established risk factors and worst prognosis.2 Ovarian cancer typically presents at an advanced stage and while initial chemotherapy response rates are favorable, a majority of patients experience recurrence with the subsequent development of chemoresistance.1 Treatment of platinum-resistant ovarian cancer is particularly challenging, with less than 15% of patients responding to subsequent chemotherapy.9

On June 5, 2022 HOOKIPA Pharma Inc. (NASDAQ: HOOK, ‘HOOKIPA’), a company developing a new class of immunotherapeutics based on its proprietary arenavirus platform, reported positive Phase 1 results from its HB-200 program evaluating single-vector HB-201 and alternating 2-vector HB-202/HB-201 in advanced Human Papillomavirus 16-positive (HPV16+) head and neck cancer patients (Press release, Hookipa Pharma, JUN 5, 2022, View Source [SID1234615563]). HB-200 was generally well tolerated, rapidly induced a high magnitude of tumor-specific T cells and showed early anti-tumor activity in these difficult-to-treat patients. The company also announced the recommended Phase 2 dose for alternating 2-vector HB-202/HB-201, which showed superior immune and tumor response compared to single-vector HB-201. The data were presented in a poster presentation (abstract #2517) at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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"We’re pleased to report the positive Phase 1 data on our novel arenaviral immunotherapies for advanced head and neck cancers, which highlight the ability of our platform technology to induce a high magnitude of potent, tumor-specific T cell responses," said Joern Aldag, Chief Executive Officer at HOOKIPA. "We’re encouraged by the superior immune response generated by alternating 2-vector immunotherapy, which resulted in an 80 percent disease control rate in patients who have failed several previous regimens. These results help focus our efforts as we move HB-202/HB-201 at the recommended Phase 2 dose into the Phase 2 portion of the trial. The findings on our alternating 2-vector technology also help inform our development plans across our oncology portfolio and especially for our HB-300 program in prostate cancer."

HB-200 Phase 1 results (NCT04180215)
Sixty-eight patients with advanced HPV16+ cancers were treated in the Phase 1 trial as of March 31, 2022. Fifty-four patients had advanced HPV16+ head and neck cancers with a median of three prior therapies (range of 1-11), including a checkpoint inhibitor regimen in 50 of the 54. Of these sixty-eight patients, five were continuing on treatment as of the cut-off date.

Safety
Phase 1 results showed HB-200 was generally well tolerated, with comparable safety between the single-vector HB-201 and alternating 2-vector HB-202/HB-201. The most common treatment-related side effects were flu-like symptoms, with only 8.8 percent of patients experiencing treatment-related side effects rated grade 3 or higher. This favorable tolerability profile in heavily pre-treated patients highlights the potential for combination with checkpoint inhibitors and other agents.

Anti-tumor activity
The poster presented at ASCO (Free ASCO Whitepaper) provided updated anti-tumor activity on 43 Phase 1 patients with HPV16+ HNSCC who received therapy intravenously every three weeks for the first five doses and every six weeks thereafter, which is the route and frequency selected for further evaluation in Phase 2 cohorts. The 43 patients were comprised of 20 persons who received single-vector HB-201 and 23 who received alternating 2-vector HB-202/HB-201.

While promising anti-tumor activity was shown in both groups, alternating 2-vector HB-202/HB-201 showed superior tumor response with 56 percent of treated patients showing target lesion shrinkage compared to 38 percent of HB-201 recipients. In addition, decreases in visceral lesions were predominantly seen in patients who received 2-vector therapy: 59 percent of patients on HB-202/HB-201 compared to 18 percent on HB-201. Further, HB-202/HB-201 demonstrated an 80 percent disease control rate, which compares favorably to historical disease control rates achieved by pembrolizumab in recurrent/metastatic HNSCC patients, specifically 35 percent overall and 40 percent in the HPV+ subset, based on peer-reviewed published data.1

T cell data
While both HB-201 and alternating 2-vector HB-202/HB-201 were highly immunogenic, HB-202/HB-201 induced superior immune response with 32 percent of recipients achieving tumor-specific T cell levels greater than 5 percent of the circulating T cell pool (7 percent of HB-201 recipients achieved this threshold). Tumor specific T cells are essential in eradicating cancer cells.

"Patients with advanced head and neck cancers have limited options," said Siqing Fu, M.D., Ph.D., professor of Investigational Cancer Therapeutics and principal investigator at The University of Texas MD Anderson Cancer Center, who presented the data at the ASCO (Free ASCO Whitepaper) meeting. "It’s encouraging to see a novel arenaviral immunotherapy demonstrate strong T cell response and anti-tumor activity in this difficult-to-treat population. I look forward to seeing future results from the Phase 2 portion in HPV16+ head and neck cancers, as well as in other types of cancer."

About HB-202/HB-201
HB-201 and HB-202/HB-201 are HOOKIPA’s lead oncology candidates engineered with the company’s proprietary replicating arenaviral vector platform. HB-201 is a single-vector compound that uses Lymphocytic Choriomeningitis Virus as its arenaviral backbone. HB-202 is a single-vector compound that uses Pichinde Virus as its arenaviral backbone. Both express the same antigen, an E7E6 fusion protein derived from HPV16. HB-202/HB-201 is an alternating 2-vector immunotherapy designed to further focus the immune response against the target antigen. In pre-clinical studies, alternating administration of HB-201 and HB-202 resulted in a ten-fold increase in immune response and better disease control than either compound alone. Both novel immunotherapy candidates, in combination with pembrolizumab, received Fast Track Designation from the U.S. Food and Drug Administration for the treatment of 1st-line advanced/metastatic HPV16+ head and neck cancers.

About the HB-200 trial (NCT04180215)
This Phase 1/2 clinical trial is an open-label trial evaluating single-vector HB-201 and alternating 2-vector HB-202/HB-201 for the treatment of advanced HPV16+ cancers who progressed on standard of care, including checkpoint inhibitors. The primary endpoint of Phase 1 was a recommended Phase 2 dose.

In Phase 1, HB-201 was evaluated at three dose levels, with two dosing schedules and two administration routes in 40 patients. HB-202/HB-201 was evaluated at four dose levels and two administration routes in 28 patients. Based on safety, anti-tumor activity and T cell response data, HB-202/HB-201 has been advanced for further development in Phase 2.

The Phase 2 part of the trial is open-label with primary endpoints of safety, tolerability and preliminary efficacy, defined by RECIST 1.1, for overall survival, progression-free survival and duration of response. Phase 2 is ongoing, evaluating HB-202/HB-201 alone in the post standard of care setting and in combination with pembrolizumab in 1st line and 2nd plus line settings. HB-201 in combination with pembrolizumab is being assessed for safety only in a small cohort. Initial results of HB-202/HB-201 in combination with pembrolizumab are anticipated in the second half of 2022 and will help inform the randomized Phase 2 trial of HB-202/HB-201 in combination with pembrolizumab planned for the first half of 2023. Initial results of HB-202/HB-201 as a post-standard of care treatment are expected in the first half of 2023.

About Human Papillomavirus-driven Cancers
Human Papillomavirus, or HPV, is a common viral infection estimated to cause about 5 percent of the worldwide cancer burden. This includes up to 60 percent of head and neck, 89 percent of cervical, 78 percent of vaginal, 88 percent of anal, 67 percent of vulvar and 50 percent of penile cancers.

While there are numerous HPV types associated with cancer, HPV16 is the most common cause of cancer. Most HPV infections are cleared from the body with no lasting consequences. However, in some cases, HPV DNA becomes integrated into chromosomal DNA. When host cells take up this DNA, they express the HPV E6 and E7 proteins. This uptake can potentially lead to cancer since expression of these proteins leads to alterations in cell cycle control, which in turn predisposes these cells to become cancerous.

On June 5, 2022 The Janssen Pharmaceutical Companies of Johnson & Johnson reported that updated efficacy and safety results from the teclistamab Phase 1/2 MajesTEC-1 study.1 Teclistamab is an investigational, off-the-shelf, T-cell redirecting bispecific antibody targeting B-cell maturation antigen (BCMA), which is being studied in patients with relapsed or refractory multiple myeloma (RRMM) (Press release, Johnson & Johnson, JUN 5, 2022, View Source [SID1234615579]).1 The data were featured as part of an oral session during the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. Applications seeking approval of teclistamab are currently under health authority review in the United States (U.S.) and Europe.

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The multicohort, open-label, Phase 1/2 MajesTEC-1 study is investigating the safety and efficacy of teclistamab in patients with RRMM who received at least three prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody.3 As of March 2022, 165 patients were treated with teclistamab at the recommended subcutaneous (SC) Phase 2 dose (RP2D) of 1.5 mg/kg preceded by step-up doses of 0.06 mg/kg and 0.3 mg/kg across both Phase 1 (NCT03145181) and Phase 2 (NCT04557098) of the study.1

Longer Follow-up from MajesTEC-1 Study in Patients with Triple Class Exposed Multiple Myeloma (Abstract #8007)

At a median follow-up of 14.1 months (range, 0.26-24.4), an overall response rate (ORR) of 63 percent (95 percent Confidence Interval [CI], range, 55.2-70.4) was observed in patients with triple class exposed multiple myeloma, with a complete response (CR) or better achieved in 39.4 percent of patients.1 Study participants had three or more prior lines of therapy, with a median of five prior lines, including a prior proteasome inhibitor, immunomodulatory drug and anti-CD38 antibody​.1 The majority of patients were triple-class refractory and/or refractory to their last line of treatment.1 Although response duration data are not mature, the median duration of response at this time is 18.4 months and has not been reached in patients who achieved a CR or better (95 percent CI, 14.9 not estimable).1 This suggests responses to teclistamab were durable and deepened over time.1 The medium progression-free survival (PFS) was 11.3 months (95 percent CI, 8.8–17.1).1 Adverse events (AEs) were low-grade for the most part and manageable with no new safety signals seen.1

These results from the MajesTEC-1 study were also simultaneously published online in The New England Journal of Medicine.2

"The longer term results from the MajesTEC-1 study suggest that patients are able to achieve deep and durable responses when treated with teclistamab," said Maria-Victoria Mateos, M.D., Ph.D., Consultant Physician in Haematology, University Hospital of Salamanca.* "These encouraging data reinforce the potential of teclistamab as a monotherapy for eligible patients with heavily pretreated multiple myeloma, in need of new treatment options."

No new safety signals were observed with longer follow-up.1 In 14.1 month follow-up data presented, the most common grade 3/4 haematologic AEs were neutropenia (64.2 percent); anaemia (37 percent); lymphopenia (32.7 percent) and thrombocytopenia (21.2 percent).1 Infections occurred in 76.4 percent of patients (44.8 percent grade 3/4).1 The most common nonhaematologic AE was cytokine release syndrome (CRS), all of which were grade 1/2 except for one transient grade 3 CRS (72.1 percent all grade).1 The median time to CRS onset was two days (range, 1-6) and median duration was two days (range, 1-9).1 There were five treatment-related deaths, and dose reductions and discontinuations due to AEs were infrequent.1

First Results from Cohort C of the MajesTEC-1 Study of Teclistamab in Patients with RRMM with Prior Exposure to BCMA Targeted Treatment (Abstract #8013)

Initial results were also presented from Cohort C of the MajesTEC-1 study evaluating teclistamab in the treatment of patients with RRMM who had previously been exposed to an anti-BCMA treatment.4 These patients had received a median of six prior lines of therapy, most (85 percent) were triple-class refractory and 35 percent were penta-drug refractory.4 The use of teclistamab following prior treatment with chimeric antigen receptor T-cell (CAR-T) therapy and/or an antibody drug conjugate (ADC) (e.g., belantamab mafodotin) targeting BCMA resulted in a promising response rate in patients with heavily pretreated RRMM.4 At a median follow-up of 12.5 months (range, 0.7-14.4), the ORR was 52.5 percent (95 percent CI, 36.1-68.5) among 40 patients who received teclistamab in Cohort C.4 Responses to teclistamab occurred early and deepened over time, with comparable response rates in patients previously treated with an ADC and/or CAR-T.4

A tolerable side-effect profile was observed in patients previously treated with anti-BCMA treatment, with no dose reductions or discontinuations due to AEs.4 The safety profile for Cohort C was comparable with that observed in BCMA treatment-naive patients, with no new safety signals.4 In 12.5 month follow-up data, 26 patients (65 percent; 30 percent grade 3/4) had infections.4 The most common AEs (n=40) were CRS (65 percent any grade), with a median time to CRS onset and duration of two days (range, 2-6) and two days (range, 1-4) respectively.4 Cytopenias (grade 3/4) were noted as follows; neutropenia (62.5 percent); thrombocytopenia (30 percent); anaemia (35 percent); and lymphopenia (42.5 percent).4

"Patients with relapsed or refractory multiple myeloma have limited treatment options and only 30 percent will be able to achieve a response using conventional therapies," said Edmond Chan MBChB M.D. (Res), EMEA Therapeutic Area Lead Haematology, Janssen-Cilag Limited. "While unmet needs remain, we continue to be dedicated to developing innovative treatment approaches that improve outcomes for people living with multiple myeloma, at all stages of the disease."

Initial Patient-Reported Health-Related Quality of Life (HRQoL) Outcomes in Patients with RRMM Treated with Teclistamab (Abstract #8033)

Initial results from an analysis of patient-reported health-related quality of life (HRQoL) outcomes following treatment with teclistamab were also shared in a poster session.5 The study analysed patient-reported assessments of quality of life metrics among patients in the MajesTEC-1 trial who had received their first treatment dose by March 18, 2021.5 The metrics analysed include function (physical, role, emotional, cognitive, social); symptoms (fatigue, nausea/vomiting, pain, appetite loss, constipation, diarrhoea); and generic health (mobility, self-care, usual activities, pain/discomfort, anxiety/depression).5 Over 80 percent of the 110 patients included in the patient-reported outcomes (PRO) analysis noted meaningful improvement (percentages of patients with clinically meaningful change from baseline (EORTC QLQ-C30 scales: ≥10 points)) in at least one of the symptom scales.5 Reduction in pain scores occurred as early as cycle two.5 At the moment, no meaningful improvement was observed in the scales for physical functioning and fatigue.5 These initial PRO results complement recent clinical data and support teclistamab as a potential off-the-shelf, T-cell redirecting therapy for patients with RRMM.5

As of September 7, 2021, median duration of treatment was 5.7 months and median follow-up was 7.8 months.5 Global health​ status scores significantly improved from baseline (95 percent CIs for least squares mean change did not cross 0) at cycles four, six, and eight; emotional functioning significantly improved at all time points.5 PRO assessments included European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 item (EORTC QLQ-C30).5 PROs were assessed on day one of each treatment cycle (28 days per cycle).5 Additional follow-up is needed to assess the full benefit of meaningful improvement in functional outcomes.5

"The updated data presented at ASCO (Free ASCO Whitepaper) support the ongoing evaluation of teclistamab for the treatment of relapsed or refractory multiple myeloma," said Yusri Elsayed, M.D., M.HSc., Ph.D., Vice President, Disease Area Leader, Hematologic Malignancies, Janssen Research & Development, LLC. "These results underscore our ongoing commitment to address the unmet need for new therapeutic options and our effort to bring forward novel treatments for multiple myeloma patients in the near future."

#ENDS#

About Teclistamab

Teclistamab is an investigational, fully humanised IgG4, T-cell redirecting, bispecific antibody targeting both BCMA and CD3, on T-cells.1 BCMA is expressed at high levels on multiple myeloma cells.6,7,8,9,10 Teclistamab redirects CD3-positive T-cells to BCMA-expressing myeloma cells to induce killing of tumor cells.11

Teclistamab is currently being evaluated in several monotherapy and combination studies.3,12,13,14,15 In 2020, the European Commission (EC) and the U.S. Food and Drug Administration (FDA) each granted teclistamab Orphan Drug Designation for the treatment of multiple myeloma. In January 2021 and June 2021, teclistamab received a PRIority MEdicines (PRIME) designation by the European Medicines Agency (EMA) and Breakthrough Therapy Designation (BTD) by the FDA, respectively. PRIME offers enhanced interaction and early dialogue to optimise drug development plans and speed up evaluation of cutting-edge, scientific advances that target a high unmet medical need.16 The U.S. FDA grants BTD to expedite the development and regulatory review of an investigational medicine that is intended to treat a serious or life-threatening condition and is based on preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.17 In December 2021, Janssen submitted a Biologics License Application (BLA) to the FDA seeking approval of teclistamab for the treatment of patients with RRMM; a marketing authorisation application (MAA) was submitted to the EMA for teclistamab approval in January 2022.

About Multiple Myeloma

Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.18 In multiple myeloma, cancerous plasma cells change and grow out of control.18 In Europe, more than 50,900 people were diagnosed with multiple myeloma in 2020, and more than 32,500 patients died.19 While some patients with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms, which can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels or kidney failure.20

On June 5, 2022 JW Therapeutics (HKEx: 2126), an independent and innovative biotechnology company focused on developing, manufacturing and commercializing cell immunotherapy products, reported the latest data of three clinical studies on Carteyva (relmacabtagene autoleucel injection, hereafter abbreviated as relma-cel) at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, including a two-year follow-up result of RELIANCE study, a multicenter phase 2 trial of Carteyva in Chinese patients with relapsed/refractory large B-cell lymphoma, preliminary safety and efficacy of Carteyva as second-line therapy for primary refractory Chinese patients with large B-cell lymphoma (LBCL) from an open-label, multicenter, single-arm phase I study, and a two-year survival update of a phase I study of Carteyva in relapsed and refractory B-cell non-Hodgkin lymphoma (Press release, JW Therapeutics, JUN 5, 2022, View Source [SID1234615596]).

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Two-year follow-up result of RELIANCE study, a multicenter phase 2 trial of relmacabtagene autoleucel in Chinese patients with relapsed/refractory large B-cell lymphoma (abstract number: 7529)

RELIANCE study was the first pivotal CD19 CAR-T study received IND approval by NMPA. A total of 59 patients with relapsed/refractory (r/r) large B-cell lymphoma (LBCL) received single infusion of relma-cel, and completed 2-year follow-up. Results include:

Relma-cel demonstrated sustained response and long-term survival benefit. Among the 58 efficacy evaluable patients, best overall response rate (ORR) and complete response rate (CRR) were 77.6% and 53.5%, respectively. 2-year overall survival (OS) rate was 69.0%.
Relma-cel showed a manageable safety profile with relatively low rate of cytokine release syndrome (CRS) and neurotoxicity (NT). The incidence of CRS of any grade and Grade≥3 were 47.5%, 5.1%, respectively. The incidence of NT of any grade and Grade≥3 were 20.3%, 3.4%, respectively. The most common Grade≥3 adverse events (AEs) were neutropenia and leukopenia.
2-year follow-up data of RELIANCE study showed that relma-cel delivered sustained response and long-term survival with a manageable safety profile and a relatively low incidence of CAR-T related toxicity.
Preliminary safety and efficacy of relmacabtagene autoleucel (relma-cel) as second-line therapy for primary refractory Chinese patients with large B-cell lymphoma (LBCL): Results from an open-label, multicenter, single-arm phase I study (abstract number: e19509)

This was an open-label, single-arm, multi-centre, phase I study, aiming to evaluate the safety and efficacy of relma-cel in patients with primary refractory disease after first-line standard of care (R-CHOP). A total of 12 patients received relma-cel infusion and completed 9 months follow-up.

Data showed relma-cel was tolerable. No Grade≥3 CRS or NT was observed. 6 patients had Grade ≤2 CRS, and 2 patients experienced NT (Grade 1). The most common treatment related Grade≥3 treatment emergent adverse events (TEAEs) was cytopenia.

The best ORR and CRR were 75.0% and 33.3%, 3-month ORR and CRR were 41.7% and 33.3%, respectively. Median duration of response (DOR) and OS were not yet reached.

Relma-cel (JWCAR029) in relapsed and refractory B-cell non-Hodgkin lymphoma: A two-year survival update of a phase I study (abstract number: e19555)

This was an open-label, dose-escalating phase I study of relma-cel for relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). A total of 22 patients with r/r B-NHL received single dose of relma-cel and completed 2-year follow-up.

Based on the efficacy analysis set comprising 20 patients, the best ORR and CRR were 85.00% and 70.00%, respectively. The progression-free survival (PFS) rates of 1-year and 2-year were both 55.0%, and the OS rates were both 68.6%. Neither median PFS nor median OS was reached. No grade 3 and above CRS or NT were found.

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About Relmacabtagene Autoleucel Injection (trade name: Carteyva)

Relmacabtagene autoleucel injection (abbreviated as relma-cel, trade name: Carteyva) is an autologous anti-CD19 CAR-T cell immunotherapy product independently developed by JW Therapeutics based on a CAR-T cell process platform of Juno Therapeutics (a Bristol Myers Squibb company). Being the first product of JW Therapeutics, relma-cel was approved by the China National Medical Products Administration (NMPA) in September 2021 for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, making it the first CAR-T product approved as Category 1 biologics product in China. Currently, it is the only CAR-T product in China that has been simultaneously included in the National Significant New Drug Development Program, granted priority review and breakthrough therapy designations.