On December 8, 2023 Pfizer Inc. (NYSE:PFE) reported the European Commission (EC) has granted conditional marketing authorization for ELREXFIO (elranatamab). ELREFXIO is a targeted immunotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma (RRMM) who have received at least three prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody and have demonstrated disease progression on the last therapy (Press release, Pfizer, DEC 8, 2023, View Source [SID1234638356]). ELREXFIO is an off-the-shelf (ready-to-use) B-cell maturation antigen (BCMA)-CD3-directed bispecific antibody (BsAb) immunotherapy that induces deep and durable responses, with a manageable tolerability profile as well as convenient subcutaneous dosing.

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"More than 50,000 Europeans are diagnosed with multiple myeloma each year, and too often, they face relapse and treatment resistance," said Chris Boshoff, Chief Oncology Research and Development Officer and Executive Vice President, Pfizer. "Today’s approval provides a new, broadly available option for people with hard-to-treat multiple myeloma, and we continue to explore the use of ELREXFIO in earlier lines of treatment so that more people may ultimately benefit from this therapy."

The conditional marketing authorization for ELREXFIO is valid in all 27 EU member states as well as Iceland, Liechtenstein, and Norway. This authorization follows the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) recommendation for a conditional marketing authorization on October 12, 2023.

Authorization was based on data from cohort A of the Phase 2 MagnetisMM-3 study (NCT04649359) showing meaningful responses among heavily pretreated RRMM patients – at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody – who received ELREXFIO as their first BCMA-directed therapy. In an analysis of these patients (n=123), the objective response rate was 61%, with a 71% probability of maintaining a response at 15 months.

The results from MagnetisMM-3 also established once-every-other-week dosing with ELREXFIO for all responding patients after 24 weeks of weekly therapy, which means less time at the clinic and potentially greater long-term treatment tolerability. Among responding patients who switched to every-other-week dosing at least six months prior to the data cut-off date (n=50), 80% maintained or improved their response after the switch, with 38% attaining a complete response (CR) or better after the switch. These data were published in Nature Medicine.

The most common adverse reactions to ELREXFIO are cytokine release syndrome (CRS) (58%), anemia (54%), neutropenia (45%), fatigue (44%), upper respiratory tract infection (39%), injection site reaction (38%), diarrhea (38%), pneumonia (37%), thrombocytopenia (36%), lymphopenia (30%), decreased appetite (27%), rash (26%), joint pain (arthralgia) (25%), fever (pyrexia) (27%), hypokalemia (23%), nausea (21%), and dry skin (21%). Serious adverse reactions are pneumonia (31%), sepsis (15%), CRS (13%), anemia (6%), upper respiratory tract infection (5%), urinary tract infection (3%), febrile neutropenia (3%), dyspnea (2%), and pyrexia (2%). Most cases of CRS were Grade 1 (44% of patients), with Grade 2 in 14% and Grade 3 in less than 1% of patients.

Due to the risk of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), patients should be monitored for signs and symptoms for 48 hours after administration of each of the two step-up doses within the ELREXFIO dosing schedule and instructed to remain in proximity of a healthcare facility. In the EU, precautionary hospitalization is not required. Patients are not required to stay near a healthcare facility for the 76-mg first treatment dose.

About Multiple Myeloma

Multiple myeloma (MM) is an aggressive and currently incurable blood cancer that affects plasma cells made in the bone marrow. Healthy plasma cells make antibodies that help the body fight infection.1 MM is the second most common type of blood cancer, with over 50,000 new cases diagnosed annually in Europe and 176,000 new cases diagnosed globally each year.2,3 About 40% of those diagnosed with MM won’t survive beyond five years,4 and most will receive four or more lines of therapy due to relapse.5 While disease trajectory varies for each person, relapses are nearly inevitable.6 The goal of therapy for people with RRMM is to achieve disease control with acceptable toxicity and improved quality of life.7

About ELREXFIO (elranatamab)

ELREXFIO is a subcutaneously delivered B-cell maturation antigen (BCMA)-CD3-directed bispecific antibody (BsAb) immunotherapy that binds to BCMA on myeloma cells and CD3 on T-cells, activating the T-cells to kill myeloma cells.

In August 2023, ELREXFIO was approved by the U.S. Food and Drug Administration (FDA) under its Accelerated Approval Program, which allows for earlier approval of drugs that treat serious conditions and fill an unmet medical need. ELREXFIO has also received approval in Switzerland and Brazil under Project Orbis, a framework for the concurrent submission and review of oncology drugs among international partners to potentially expedite approvals. Three other countries (Canada, Australia, and Singapore) are participating in Project Orbis. The UK Medicines and Healthcare Products Regulatory Agency (MHRA) has granted ELREXFIO Innovative Medicine Designation and the Innovation Passport for the treatment of MM.

Pfizer’s extensive MagnetisMM clinical development program is continuing to investigate ELREXFIO’s use across the entire spectrum of patients with MM, from RRMM to newly diagnosed MM. Ongoing registrational-intent trials are exploring ELREXFIO both as monotherapy and in combination with standard or novel therapies. These include MagnetisMM-5 in the double-class exposed setting, MagnetisMM-6 in newly diagnosed patients who are ineligible for stem cell transplant, and MagnetisMM-7 in newly diagnosed patients after transplant.

Detailed information on this medicinal product is available on the website of the European Medicines Agency View Source

U.S. INDICATION

ELREXFIO may cause side effects that are serious, life-threatening, or can lead to death, including cytokine release syndrome (CRS) and neurologic problems. CRS is common during treatment with ELREXFIO.

Tell your healthcare provider or get medical help right away if you develop any signs or symptoms of CRS or neurologic problems, including:

fever of 100.4°F (38°C) or higher
trouble breathing
chills
dizziness or light-headedness
fast heartbeat
headache
increased liver enzymes in your blood
agitation, trouble staying awake, confusion or disorientation, or seeing or hearing things that are not real (hallucinations)
trouble speaking, thinking, remembering things, paying attention, or understanding things
problems walking, muscle weakness, shaking (tremors), loss of balance, or muscle spasms
numbness and tingling (feeling like "pins and needles")
burning, throbbing, or stabbing pain
changes in your handwriting
Due to the risk of CRS, you will receive ELREXFIO on a "step-up" dosing schedule and should be hospitalized for 48 hours after the first "step-up" dose and for 24 hours after the second "step-up" dose of ELREXFIO.

For your first dose, you will receive a smaller "step-up" dose of ELREXFIO on day 1
For your second dose, you will receive a larger "step-up" dose of ELREXFIO, which is usually given on day 4 of treatment
For your third dose, you will receive the first "treatment" dose of ELREXFIO, which is usually given on day 8
If your dose of ELREXFIO is delayed for any reason, you may need to repeat step-up dosing. Before each dose of ELREXFIO you receive during the step-up dosing schedule, you will receive medicines to help reduce your risk of CRS. Your healthcare provider will decide if you need to receive medicines to help reduce your risk of CRS with future doses.

ELREXFIO is available only through the ELREXFIO Risk Evaluation and Mitigation Strategy (REMS) Program due to the risk of CRS and neurologic problems. You will receive an ELREXFIO Patient Wallet Card from your healthcare provider. Carry the ELREXFIO Patient Wallet Card with you at all times and show it to all of your healthcare providers. The ELREXFIO Patient Wallet Card lists signs and symptoms of CRS and neurologic problems. Get medical help right away if you develop any of the signs and symptoms listed on the ELREXFIO Patient Wallet Card. You may need to be treated in a hospital.

Before taking ELREXFIO, tell your healthcare provider about all of your medical conditions, including if you:

have an infection
are pregnant or plan to become pregnant. ELREXFIO may harm your unborn baby. Females who are able to become pregnant should do a pregnancy test before starting treatment with ELREXFIO and should use effective birth control during treatment and for 4 months after your last dose of ELREXFIO. Tell your healthcare provider right away if you become pregnant or think that you may be pregnant during treatment with ELREXFIO
are breastfeeding or plan to breastfeed. It is not known if ELREXFIO passes into your breast milk. Do not breastfeed during treatment and for 4 months after your last dose of ELREXFIO
Tell your healthcare provider about all of the medications you take, including prescription and over-the-counter medications, vitamins, and herbal supplements.

Do not drive, operate heavy or potentially dangerous machinery, or do other dangerous activities during treatment with ELREXFIO:

for 48 hours after completing each of the 2 doses of ELREXFIO that are part of the "step-up dosing schedule" and your first full treatment dose, and
at any time during treatment with ELREXFIO if you develop any new neurologic symptoms, such as dizziness, confusion, shaking (tremors), sleepiness, or any other symptom that impairs consciousness, until the symptoms go away.
Infections: Upper respiratory tract infection and pneumonia are common during treatment with ELREXFIO. ELREXFIO can cause bacterial and viral infections that are severe, life-threatening, or that may lead to death.

Your healthcare provider may prescribe medications for you to help prevent infections and treat you as needed if you develop an infection during treatment with ELREXFIO
Tell your healthcare provider right away if you develop any signs or symptoms of an infection during treatment with ELREXFIO, including: fever of 100.4°F (38°C) or higher, chills, cough, shortness of breath, chest pain, sore throat, pain during urination, or feeling weak or generally unwell
People with active infections should not start ELREXFIO
Decreased white blood cell counts: Decreased white blood cell counts are common during treatment with ELREXFIO and can also be severe. A fever can occur with low white blood cell counts and may be a sign that you have an infection. Your healthcare provider will treat you as needed.

Liver problems: ELREXFIO can cause increased liver enzymes and bilirubin in your blood. These increases can happen with or without you also having CRS. Tell your healthcare provider if you develop any of the following signs or symptoms of a liver problem, including:

tiredness
loss of appetite
pain in your right upper stomach-area
dark urine
yellowing of your skin or the white part of your eyes
The most common side effects of ELREXFIO include:

tiredness
injection site reaction, such as redness, itching, pain, bruising, rash, swelling, and tenderness
diarrhea
muscle and bone pain
decreased appetite
rash
cough
nausea
fever
The most common severe abnormal lab test results with ELREXFIO include decreased white blood cells, red blood cells, and platelets.

Your healthcare provider may temporarily or permanently stop ELREXFIO if you have any of the side effects listed and they are severe. These are not all of the possible side effects of ELREXFIO.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is ELREXFIO?

ELREXFIO is a prescription medication used to treat adults with multiple myeloma who:

have already received at least 4 treatment regimens, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, to treat their multiple myeloma, and
their cancer has come back or did not respond to prior treatment.
ELREXFIO was approved based on patient responses and durability of response. There are ongoing studies to confirm its clinical benefit. It is not known if ELREXFIO is safe and effective in children.

Please read full Prescribing Information, including BOXED WARNING, for ELREXFIO.

On December 8, 2023 NiKang Therapeutics Inc. ("NiKang"), a clinical stage biotech company focused on developing innovative small molecule oncology medicines to help patients with unmet medical needs, reported that it has entered into a clinical trial collaboration and supply agreement with F. Hoffmann-La Roche Ltd. ("Roche") to evaluate NKT2152, a small molecule that inhibits hypoxia inducible factor 2α (HIF2α), in combination with standard-of-care atezolizumab (Tecentriq) and bevacizumab (Avastin) in first-line treatment of unresectable/advanced hepatocellular carcinoma (HCC) (Press release, NiKang Therapeutics, DEC 8, 2023, View Source [SID1234638355]). This collaboration will utilize Roche’s MORPHEUS-LIVER phase 1b/2 platform for rapid and efficient combination development.

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This randomized multi-regional phase 1b/2 trial is intended to evaluate the efficacy and safety of NKT2152 in combination with atezolizumab and bevacizumab versus atezolizumab and bevacizumab in patients with unresectable/advanced HCC not previously treated with systemic therapy. Patient enrollment will begin in 2024. Under the collaboration, Roche will sponsor the study, and each company will supply its respective anti-cancer agent to support the trial. NiKang retains its development and commercialization rights of NKT2152. Additional financial details of the agreement were not disclosed.

"We are thrilled to enter this collaboration with Roche, which allows us to explore the broader potential of our HIF2α inhibitor NKT2152 in treating solid tumors beyond clear cell Renal Cell Carcinoma (ccRCC)," said Zhenhai Gao, Ph.D., co-founder, president, and CEO of NiKang. "Based on the compelling scientific rationale and supporting preclinical studies, we have a keen interest in assessing NKT2152 in HCC patients. This collaboration enables us to leverage Roche’s MORPHEUS-LIVER phase 1b/2 platform to explore this promising opportunity expeditiously."

NKT2152 is currently in a phase 1/2 dose escalation and expansion trial (NCT05119335) that is designed to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics and clinical activity in patients with advanced ccRCC.

On December 8, 2023 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported positive long-term follow-up data from the pivotal, Phase III KATHERINE study in people with HER2-positive early-stage breast cancer (eBC) who have residual invasive disease following neoadjuvant (before surgery) treatment (Press release, Genentech, DEC 8, 2023, View Source [SID1234638354]). A statistically significant and clinically meaningful improvement in overall survival (OS), a secondary endpoint, was observed with adjuvant (post-surgery) Kadcyla (ado-trastuzumab emtansine) compared to Herceptin (trastuzumab): at the 7-year landmark OS rates were 89.07% and 84.37% with Kadcyla and Herceptin, respectively (hazard ratio [HR]=0.66, 95% CI: (0.51, 0.87), p-value =0.0027). Data also show that the previously reported invasive disease-free survival (primary endpoint) benefit is maintained. Kadcyla reduced the risk of disease recurrence or death from any cause by 46% compared to Herceptin (HR=0.54, 95% CI: (0.44, 0.66), p-value <0.0001), strengthening the results of the primary analysis of KATHERINE. The safety profile of Kadcyla was consistent with previous findings and no new safety signals were identified.

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"We are pleased that Kadcyla could offer people with HER2-positive early breast cancer with a particularly poor prognosis a chance to live longer and without recurrence of their disease," said Levi Garraway, M.D., Ph.D., Genentech’s chief medical officer and head of Global Product Development. "The ultimate goal of treating early breast cancer is to maximize the chance of cure, and these results signify an important step forward for these patients."

"Thanks to remarkable advances in diagnostics and treatment, more women are surviving an initial diagnosis of HER2-positive early-stage breast cancer than ever before. However, in those with higher risk disease, recurrence and long-term survival have remained a challenge," said Prof. Dr. Sibylle Loibl, Chair of the German Breast Group (GBG), Principal Investigator of KATHERINE. "With these new data, Kadcyla is the first targeted therapy to demonstrate a significant survival benefit in people with HER2-positive early breast cancer with residual invasive disease after neoadjuvant treatment."

The KATHERINE study has been conducted in collaboration with the GBG and NSABP Foundation, Inc. Full data are being presented as an oral presentation at the 2023 San Antonio Breast Cancer Symposium on Friday, December 8.

Kadcyla is approved in 113 countries and is the standard of care for people with HER2-positive eBC with residual invasive disease following neoadjuvant treatment, based on previous positive results from KATHERINE that showed Kadcyla cut the risk of disease recurrence or death by half versus Herceptin. Additionally, at three years, 88.3% of people treated with Kadcyla did not have their breast cancer return compared to 77.0% treated with Herceptin, an absolute improvement of 11.3%.

Breast cancer is the most frequently diagnosed type of cancer, with major societal impact. Approximately one in five people with breast cancer will be HER2-positive, a particularly aggressive form of the disease. The goal in treating eBC is to provide people with the best chance for a cure. While we come closer to this goal with each advance, many people still have disease recurrence in the long-term and more personalized treatment options are needed to reduce this risk and help people live longer.

Kadcyla is also approved for the treatment of people with HER2-positive metastatic breast cancer who previously received trastuzumab and a taxane.

About the KATHERINE Study

KATHERINE is an international, multi-center, two-arm, randomized, open-label, Phase III study evaluating the efficacy and safety of Kadcyla versus Herceptin as an adjuvant therapy in people with HER2-positive early-stage breast cancer who have residual invasive disease following neoadjuvant therapy that included Herceptin and taxane-based chemotherapy. In KATHERINE, residual invasive disease was defined as the presence of invasive residual disease in tissue samples from breast and/or axillary nodes following neoadjuvant treatment. People who have residual invasive disease after neoadjuvant treatment generally have a worse prognosis than those without detectable disease at surgery.

The primary endpoint of the study is invasive disease-free survival which, in this study, is defined as the time from randomization free from invasive breast cancer recurrence or death from any cause. Secondary endpoints include DFS and overall survival.

About HER2-positive breast cancer

Breast cancer is one of the most common cancers among women worldwide. Breast cancer is not one, but many diseases based on the biology of each tumor. In HER2-positive breast cancer, there is excess HER2 protein on the surface of tumor cells. Approximately 15-20% of breast cancers are HER2-positive based on the result of a diagnostic test.

About Kadcyla

Kadcyla is an antibody-drug conjugate (ADC) engineered to deliver potent chemotherapy directly to HER2-positive cancer cells. It is designed to limit damage to healthy tissues, although it can still affect them. Kadcyla can cause serious side effects. It combines two anti-cancer agents using a stable linker: the HER2-targeting trastuzumab (the active ingredient in Herceptin) and the chemotherapy agent DM1. Kadcyla is the only ADC approved for the treatment of HER2-positive early and metastatic breast cancer. In the U.S., Genentech licenses technology for Kadcyla under an agreement with ImmunoGen, Inc.

On December 8, 2023 City of Hope, one of the largest cancer research and treatment organizations in the United States, reported that it will present innovative research at this year’s San Antonio Breast Cancer Symposium (SABCS), taking place Dec. 5 to 9 in San Antonio, Texas (Press release, City of Hope, DEC 8, 2023, View Source [SID1234638353]).

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Each year, about 10,000 physicians, scientists and other health care professionals attend the annual conference, which examines new breast cancer research and helps guide treatment of patients nationwide. It is the largest and most prestigious scientific gathering on breast cancer research.

Research presented by City of Hope doctors and scientists includes:

Study: Data shows that taking estrogen reduces breast cancer risk in postmenopausal women who had a hysterectomy

Data from the Women’s Health Initiative (WHI) in 2002 had this finding: Women without a uterus who took estrogen and progesterone, hormone replacement therapy that women took to help prevent health problems caused by menopause, had an increased risk of breast cancer compared to those women in the study who took a placebo. The use of hormone replacement therapy dropped drastically. Women who had a uterus and only took estrogen had a lower incidence of breast cancer compared to women who took the placebo, but those findings were challenged and have been debated since then.

City of Hope’s Joanne Mortimer, M.D., director of the Women’s Cancers Program, Baum Family Professor in Women’s Cancers and vice chair/professor, Department of Medical Oncology & Therapeutics Research, and other breast cancer doctors and scientists from other institutions decided to take a deeper dive into those findings. They gathered data from nine other smaller studies of women who had a hysterectomy and took estrogen to compare those results with WHI data, which now tracks breast cancer incidence after more than 20 years of data collection.

The analysis of 7,339 women showed a lower risk of developing breast cancer among the women with no uterus who took estrogen compared with those who took a placebo. However, hormone replacement therapy did not strongly protect women in the studies against such menopause-related health complications as cardiovascular disease and brain health.

"Postmenopausal women who took a combination of estrogen and progesterone have a higher risk for developing breast cancer," said Mortimer, who will present the research at SABCS. "This study shows that single agent estrogen is safe in the population of women who have undergone hysterectomy and who desire hormone replacement therapy."

The abstract titled "Randomized trials of estrogen-alone and breast cancer incidence: a meta-analysis" was presented Dec. 6 in an oral presentation spotlight.

Findings from City of Hope’s innovative Couples Coping With Cancer Together program

Research from City of Hope’s innovative Couples Coping With Cancer Together program, started by the Department of Supportive Care Medicine, is one of the only programs of its kind nationwide, and is offered as part of the normal continuum of care provided to patients and families at City of Hope. It is tailored to the unique needs of English and Spanish-speaking couples facing a cancer diagnosis together, regardless of sexual orientation or relationship status.

As part of the supportive cancer care program, metastatic breast cancer patients and their partners completed a biopsychosocial screening, which asks each person about their perception of the patient’s prognosis. In addition, the couples were offered a standardized couples’ session before the medical consultation, individual couples’ counseling and a strengths-based group intervention.

The study included 241 patients and their partners. It found that patients were more realistic about their prognosis than their partners.

"Because open communication is important among women being treated for metastatic breast cancer and their partners, a prognosis question for both the patient and her partner should be included in standard of care," said Mortimer, who presented the research at SABCS. "This will also help couples prepare for advanced care planning."

The abstract titled "The ‘Couples Coping with Cancer Together Program’ provides insight into individual’s distress and an opportunity to discuss prognosis in a manner that is normalized as standard of care" was presented Dec. 7 in a poster session.

Testing for genetic mutations that can cause breast cancer

Because African American and Latina women have been less likely to undergo germline testing, which detects inherited genetic mutations that may cause cancer, it has been difficult to determine the prevalence of hereditary breast cancer predisposition in these populations.

Mortimer and team analyzed the prevalence of BRCA1/2 mutation in patients with a breast cancer diagnosis from City of Hope’s Implementing Next-generation Sequencing for Precision Intervention and Risk Evaluation (INSPIRE) study.

Patients with a history of any stage breast cancer were approached for their consent to undergo germline testing for 155 predisposition genes for cancer, which is performed at no cost to the patient.

From July 2020 to April 2023, 2,413 women underwent germline testing. Mutations in BRCA1 were identified in 3% of Hispanic women compared with 1.7% of non-Hispanic women. BRCA2 mutations were identified in 2.2% of Hispanics and 3% of non-Hispanics.

Hispanic women with breast cancer were 2.49 times as likely as non-Hispanics to carry a pathogenic germline BRCA1 mutations than BRCA2.

Women who have BRCA1 tend to have more aggressive breast cancers and the mutation can also cause ovarian cancer.

"What this study demonstrated is that regardless of your race, your ethnicity or age, everybody should have genetic testing," Mortimer added. "Because knowing what your BRCA status is has implications for surgery, prognosis and treatment."

"Prevalence of BRCA1/2 mutations in an underrepresented population of women with breast cancer: Observations from the City of Hope INSPIRE study" was part of a poster presentation on Dec. 7.

On December 8, 2023 Intensity Therapeutics, Inc. (Nasdaq: INTS), a clinical-stage biotechnology company focused on the discovery and development of proprietary, novel immune-based intratumoral cancer therapies designed to kill tumors and increase immune system recognition of cancers, reported that safety, tolerability, efficacy and immune activation data from the company’s Phase 2 INVINCIBLE trial of INT230-6 in patients with early-stage breast cancer without chemotherapy was presented at a Podium Poster Spotlight discussion session today during the 2023 San Antonio Breast Cancer Symposium (SABCS) (Press release, Intensity Therapeutics, DEC 8, 2023, View Source [SID1234638352]). Information on the presentation is below.

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Concurrent Poster Spotlight Session Block #6
PS16 Enhancing Immunotherapy for Triple Negative Breast Cancer: Novel Therapies and Biomarkers
Moderator: Hope S. Rugo, MD, FASCO, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California
Title: Intra-tumoral dosing of INT230-6 in early-stage breast cancer patients induces tumor cell necrosis and immunomodulatory effects: A phase II randomized window-of-opportunity study – the INVINCIBLE trial
Presentation #: PS16-03
Date and Time: Friday, December 8, 7:00 – 8:00 a.m. CT
Location: Stars at Night Ballroom 3 & 4
Presenter: Angel Arnaout, M.D., MSc, Ottawa Hospital Research Institute, Ontario Institute for Cancer Research
Discussant: Sangeetha Reddy, M.D., M.S.C.I., UT Southwestern Medical Center, Dallas, Texas

Copies of the presentation materials are available on Intensity’s website on the publications, papers and posters page.

"A large unmet need in the treatment of breast cancer is that the majority of breast cancers are immune quiescent; resulting in minimal response to immunotherapies. INT230-6 has the potential to fill this unmet need for multiple subtypes, including triple negative breast cancer, through its unique multiple anti-cancer mechanisms of action that cause tumor cell necrosis, ignition of an anti-cancer immune-based activation, increasing the diversity of the T-cell repertoire systemically that can enter into the tumor and its microenvironment," said Angel Arnaout, M.D.,MSc., Breast Surgical Oncologist at the Ottawa Hospital, Scientist at the Ottawa Hospital Research Institute, Professor of Surgery at the University of Ottawa and Co-Lead of the Ontario Institute for Cancer Research’s Window-of-Opportunity Network. "The ability for INT230-6 to induce necrosis and noted immune effects prior to a patient’s surgery, while maintaining a favorable safety profile, would be a major move forward for the treatment paradigm of breast cancer and potentially many other cancers."

"I am encouraged by the immune-related data being reported and the potential of INT230-6 as a presurgical treatment for women suffering from early-stage breast cancer," said Melanie Spears, Ph.D., Co-Director of Diagnostic Development and Co-Lead of the Window-of-Opportunity Network at the Ontario Institute for Cancer Research. "The localized effect of increased CD4 T-cells and NK cells within injected tumors and systemically increased T-cell diversity from baseline in these patients is quite interesting and remarkable for a locally-delivered therapy."

The INVINCIBLE Trial is a Phase 2, randomized study that enrolled women with newly diagnosed, operable early-stage intermediate or high-grade T1-T2 invasive breast cancers 2 to 5 weeks prior to surgery (lumpectomy or mastectomy). Drug dose was set by the diameter of the tumor. Subjects were randomly allocated (2:1) prior to resection to 1-3 IT injections of INT230-6 versus either no treatment (part 1 N=29) or saline sham injection (part 2 N=58). Several markers normally associated with systemic treatment were evaluated.

Efficacy Data:
The INVINCIBLE Phase 2 trial of INT230-6 demonstrated a high order of necrosis in presurgical breast cancer tumors in the period from diagnosis to surgery, with some patients in the Phase 2 study experiencing greater than 95% necrosis of the tumor. A functional pathway enrichment analysis was conducted and confirmed positive changes in T-cell activation, lymphocyte activation and inflammatory response. Further, INT230-6 treated patients experienced differential gene expression with an increase in median clonal diversity compared to baseline as well as significant changes in the immune cell composition, including CD4 T-cell and NK cells.

Safety Data:
Data show that INT230-6 has a favorable safety profile and is well tolerated. Over 95% of treatment-emergent adverse events (TEAEs) were low grade 1 or 2 primarily localized pain, fatigue, and nausea.

"We continue to be impressed with the safety and efficacy of INT230-6. Today’s news about the increase in mean systemic T-cell clonal diversity is truly exciting because it is a signal of the strength of adaptive immune response systemically. We believe that the ability to cause large levels of necrosis on a single dose of our locally-delivered drug with immune effects in a relatively cold cancer type such as breast cancer prior to surgery shortly after diagnosis is truly a new weapon in the war on cancer," said Lewis H. Bender, President and Chief Executive Officer of Intensity. "In addition to our anticipated Phase 3 program in metastatic sarcoma using INT230-6 as a monotherapy, we are underway in our preparations for a Phase 2/3 clinical program to test INT230-6 in combination with standard of care neoadjuvant therapy. We see the potential opportunity for our technology and drug products in both the metastatic and presurgical settings for many types of cancers."

About T-Cell Repertoire
The adaptive immune system is one of the body’s most powerful defenses. By being able to adapt, the body’s immune cells can be trained to attack undesirable cells or viruses anywhere in the body. T-cells are an important systemic component of the adaptive immune system that aid in the destruction of invaders. Immune repertoire refers to all the unique T-cell receptor (TCR) and B-cell receptor (BCR) genetic rearrangements. Only lymphocytes that encounter an antigen with the right receptor to bind to it will be activated and proliferate during an immune response, forming a clone of cells with identical antigen receptors for attack. A greater diversity of T-cell repertoire means there is higher likelihood for a T-cell to bind to the foreign entity (e.g. cancer cells) and increase the specific T-cell clonal population to destroy the invader.

About INT230-6
INT230-6, Intensity’s lead proprietary investigational product candidate, is designed for direct intratumoral injection. INT230-6 was discovered using Intensity’s proprietary DfuseRx℠ technology platform. The drug is composed of two proven, potent anti-cancer agents, cisplatin and vinblastine, and a penetration enhancer molecule (SHAO) that helps disperse potent cytotoxic drugs throughout tumors for diffusion into cancer cells. These agents remain in the tumor resulting in a favorable safety profile. In addition to local disease control, direct killing of the tumor by INT230-6 releases a bolus of neoantigens specific to the patient’s malignancy, leading to engagement of the immune system and systemic anti-tumor effects. Importantly, these effects are mediated without immunosuppression that so often occurs with systemic chemotherapy.