On June 4, 2021 Genocea Biosciences, Inc. (NASDAQ: GNCA), a biopharmaceutical company developing next-generation neoantigen immunotherapies, reported that updated immunogenicity and clinical response data from the GEN-009 Phase 1 trial that continue to validate the company’s unique and differentiated approach to identifying clinically meaningful immunotherapy targets through the proprietary ATLAS selection process (Press release, Genocea Biosciences, JUN 4, 2021, View Source [SID1234583551]). Data on the neoantigen vaccine combined with PD-1 inhibition in advanced solid tumors will be shared by Maura Gillison, M.D., Ph.D., Lead Investigator, MD Anderson Cancer Center, during a poster presentation (Abstract #2613) at the virtual 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting from June 4-8, 2021. The poster is available for on-demand viewing on the ASCO (Free ASCO Whitepaper) website and also posted to the Scientific Resources section of the Genocea website at View Source
Long-term results demonstrate that GEN-009 continues to generate broad immune responses against neoantigens that can lead to sustained clinical responses. In Part A of the study, designed to measure safety and immunogenicity only, eight patients with no measurable disease were vaccinated with GEN-009 as a monotherapy. Six of the eight patients continue without recurrence with a median follow up of 25 months post start of the vaccination. Notably, as previously reported, GEN-009 elicited T cell immune responses to 99% of the ATLAS-selected neoantigens, the highest seen across neoantigen vaccine programs.
In Part B, patients were enrolled at the initiation of a PD-1 checkpoint inhibitor (CPI)-based standard of care (SOC) regimen for advanced or metastatic disease; patients who were controlled on SOC and did not require alternate therapy are labeled CPI-sensitive, patients who required alternate therapy before vaccination are labeled CPI-refractory. Of the nine CPI-sensitive patients, the latest data show four patients experienced novel reduction in tumor volume post-GEN-009 dosing and achieved independent RECIST responses after vaccination, including three partial responses (PRs) and one complete response (CR). This is an increase from the two PRs and one CR previously reported at SITC (Free SITC Whitepaper) 2020. The remaining five CPI-sensitive patients all achieved disease stabilization. Across the CPI-sensitive cohort, the median duration without disease progression after initial GEN-009 vaccination was 15 months. Of the seven CPI-refractory patients, two achieved stable disease after initial GEN-009 vaccination for up to 10 months. GEN-009 has been well tolerated with only mild adverse events associated with the vaccine adjuvant.

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Expanded immunogenicity data from Part B of the study revealed that vaccine-specific T cell responses were detected ex vivo after the first dose of the vaccine and continued to rise with each subsequent dose. Vaccine-specific T cell responses remained significantly elevated over baseline and post-CPI, pre-vaccine timepoints for at least 6 months, showing persistence of the vaccine response. CPI-sensitive subjects had a greater number of neoantigens identified with ATLAS at baseline compared with patients in the CPI-refractory cohort, and also had evidence of epitope spread for CD8+ T cells post-dosing. Additionally, the magnitude of CD4+ T cell responses were greater for the CPI-refractory than CPI-sensitive subjects, despite a reduced proportion of peptides to which CD4+ T cell responses were measured, suggesting that the breadth and not the magnitude of response could be associated with favorable outcomes.
"We are very encouraged that GEN-009 can generate broad and diverse immune responses through ATLAS-selected neoantigens" said Thomas Davis, M.D., Chief Medical Officer of Genocea. "The deepened and durable responses in the CPI-sensitive patients and durable disease control in refractory patients are notable. We believe the cumulative long-term GEN-009 data continues to support our unique approach to identifying clinically meaningful immunotherapy targets and provides a strong foundation for our novel cell therapy candidate, GEN-011, which can target up to 30 ATLAS selected neoantigens and is currently in the clinic."
ASCO POSTER SESSION: Developmental Therapeutics – Immunotherapy
Abstract 2613: View Source
Title: Long term results from a phase 1 trial of GEN-009, a personalized neoantigen vaccine, combined with PD-1 inhibition in advanced solid tumors
GEN-009 is an adjuvanted personalized neoantigen vaccine being evaluated in eligible patients with advanced cancer who received standard-of-care (SOC) PD-1 checkpoint inhibitor (CPI) +/- chemotherapy during vaccine manufacturing and received 5 vaccine doses over 6 months along with continuation of PD-1 CPI. Genocea’s proprietary ATLAS platform selects tumor neoantigens for synthesis into GEN-009 peptides and identifies each patient’s own peripheral blood T cells and antigen-presenting cells. Patients who progressed prior to vaccination could receive alternate therapy followed by GEN-009 alone or in combination with a salvage regimen, as well as accelerated vaccine dosing. The contributions from GEN-009 are assessed using each patient as their own control based upon changes in tumor volume pre- versus post-vaccination.

On June 4, 2021 Novartis reported the first published mature overall survival (OS) and updated overall response rate (ORR) data following treatment with Tabrecta (capmatinib) in adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to MET exon 14 skipping (METex14)1-3 (Press release, Novartis, JUN 4, 2021, View Source [SID1234583567]). Data from the ongoing, pivotal, multi-cohort Phase II GEOMETRY mono-1 study will be presented today during the 2021 Annual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Meeting (Poster Discussion Session, Lung Cancer—Non-Small Cell Metastatic; June 4, 2021, 9:00 AM-10:00 AM CT; abstract 9020).

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"This new analysis further supports Tabrecta as a cornerstone targeted treatment for METex14 NSCLC patients and highlights the importance of biomarker testing," said Juergen Wolf, MD, from the Center for Integrated Oncology, University Hospital Cologne, and lead investigator of the GEOMETRY study. "The impressive overall survival outcome and confirmed outstanding response in the first-line setting will help oncologists decide upon a therapeutic option for patients."

The analysis includes new data from the treatment-naïve (1L) expansion cohort 7 and previously-treated (2L+) cohort 6, and mature data from previously-reported cohorts, for a total of 160 patients1,2.

"The introduction of Tabrecta a year ago dramatically changed the treatment landscape for patients with METex14 NSCLC. Now we have further evidence that Tabrecta, the market-leading treatment specifically for METex14 NSCLC patients4, has the potential to help people live longer," said Jeff Legos, Senior Vice President, Head of Oncology Drug Development, Novartis Oncology.

The results presented today provide additional data on the efficacy of Tabrecta in both treatment-naïve and previously-treated patients with METex14 metastatic NSCLC 2:

Overall response rate (ORR) based on the Blinded Independent Review Committee (BIRC) assessment per RECIST v1.1:
67.9% (95% CI: 47.6, 84.1) and 65.6% (95% CI: 46.8, 81.4) among treatment-naïve patients (Cohort 5b; n= 28 and Cohort 7; n= 32 patients, respectively)
40.6% (95% CI: 28.9, 53.1) and 51.6% (95% CI: 33.1, 69.8) among previously-treated patients (Cohort 4; n= 69 and Cohort 6; n= 31 patients, respectively)
Median duration of response (DOR) based on BIRC assessment:
12.6 months (95% Cl: 5.6‑NE) and NE (95% CI: 5.5-NE) among treatment-naïve patients (Cohort 5b; n= 28 and Cohort 7; n= 32 patients, respectively)
9.7 months (95% Cl: 5.6‑13.0) and 8.4 months (95% Cl: 4.2‑NE) among previously-treated patients (Cohort 4; n= 69 and Cohort 6; n= 31 patients, respectively)
Overall survival (OS):
20.8 months (95% CI: 12.42, NE [not estimated]) among treatment-naïve patients (Cohort 5b; n= 28)
13.6 months (95% CI: 8.61, 22.24) among previously-treated patients (Cohort 4; n= 69)
Median OS for expansion Cohorts 6 & 7 are not reached
No new safety signals or unexpected safety findings were observed. Ninety-eight percent of subjects had at least one adverse event (AE) of any grade and 50.9% of subjects had at least one serious adverse event (SAE). Thirteen percent were suspected to be treatment-related. The most common adverse events (>20%, all grades) across all cohorts were peripheral edema, nausea, vomiting, increased blood creatinine, dyspnea, fatigue and decreased appetite. The majority of AEs were grade 3 or 42.

Currently, the five-year survival rate for lung cancer is less than 20%5, decreasing further when the disease is diagnosed at later stages6. Nearly one in three patients with metastatic NSCLC may have an actionable mutation7,8. METex14 has been reported to occur in 3%-4% of metastatic NSCLC cases9. Many patients with mutations that lead to METex14 are not diagnosed with NSCLC until their disease has progressed to later stages and often have poor prognosis10,11.

A separate analysis of patient-reported outcomes (PROs) evaluated cough, delayed time to lung symptom deterioration, and quality of life (QoL) in NSCLC patients with METex14 (abstract 9056)3.

Median time to definitive deterioration (TTDD) in global health status (GHS) was 16.6 months (95% CI: 9.7, NE) and 12.4 months (95% CI: 4.2, 19.4) in 1L and 2L+ patients, respectively
Median TTDD for cough and chest pain was NE in both 1L and 2L+ patients, and for dyspnea was 19.4 months (95% CI: 12.4, NE) and 22.1 months (95% CI: 9.9, NE), respectively
An exploratory post hoc analysis evaluated QLQ-LC13 symptoms (cough, chest pain, and dyspnea) over time for patients achieving a clinical response, as assessed by BIRC, found these symptoms improved at all cycles in patients achieving clinical complete response (CR) or partial response, while symptom worsening was seen in those with no clinical response
Additionally, a retrospective analysis of GEOMETRY mono-1 validates the clinical utility of liquid biopsy testing to identify METex14 positive patients for treatment with Tabrecta (Poster Session: Lung Cancer—Non-Small Cell Metastatic; abstract 9111)12.

Visit View Source for the latest information from Novartis, including our commitment to the Oncology community, and access to our ASCO (Free ASCO Whitepaper)21 Virtual Scientific Program data presentations (for registered participants).

About GEOMETRY mono-1
GEOMETRY mono-1 is a Phase II a multi-center, non-randomized, open-label, multi-cohort study in adult patients with EGFR wild-type, ALK-negative rearrangement, metastatic NSCLC harboring mutations that lead to MET exon-14 skipping who received capmatinib tablets 400 mg orally twice daily.

Patients were assigned to cohorts on the basis of MET status and previous lines of therapy13. The primary endpoint was overall response rate (ORR) based on the Blinded Independent Review Committee (BIRC) assessment per RECIST v1.1. The key secondary endpoint was duration of response (DOR) evaluated by BIRC.

About Tabrecta (capmatinib)
Tabrecta (capmatinib) is a kinase inhibitor that targets MET. Tabrecta was discovered by Incyte and licensed to Novartis in 2009. Under the Agreement, Incyte granted Novartis worldwide exclusive development and commercialization rights to capmatinib and certain back-up compounds in all indications. In May 2020, Tabrecta was approved by the US Food and Drug Administration (FDA) for adult patients with metastatic NSCLC whose tumors have a mutation that leads to METex14 as detected by an FDA-approved test. This indication was approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

In June 2020, Tabrecta was approved by the Japanese Ministry of Health, Labour and Welfare (MHLW) for adult patients with metastatic NSCLC whose tumors have a mutation that leads to METex14 as detected by an FDA-approved test. Tabrecta was also approved in Hong Kong in February 2021 and Switzerland in April 2021.

Novartis and Lung Cancer
Lung cancer is the most common cancer worldwide, accounting for more than 2 million new cases diagnosed each year14. There are two main types of lung cancer – small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC)15,16. NSCLC accounts for approximately 85% of lung cancer diagnoses, resulting in nearly 2 million new cases each year14,16. More people die of lung cancer every year than any other cancer type14. Treatment options are limited for people with lung cancer who experience cancer growth or progression while on current standard of care treatments17-19.

Novartis is committed to developing best-in-class treatments for lung cancer patients around the world. With a focus on both targeted, personalized medicine and the role of newer core immuno-oncology therapies, the lung cancer drug development program at Novartis is among the most robust in the industry. Novartis research activities are informed by our long-term relationships with leading lung cancer thought leaders and patient advocates. With them, Novartis is committed to reimagining the treatment of lung cancer.

Indication
TABRECTA (capmatinib) tablets is a prescription medicine used to treat adults with a kind of lung cancer called non-small cell lung cancer (NSCLC) that has spread to other parts of the body or cannot be removed by surgery (metastatic), and whose tumors have an abnormal mesenchymal-epithelial transition (MET) gene.

The effectiveness of TABRECTA in these patients is based on a study that measured 2 types of response to treatment (response rate and duration of response). There is no clinical information available to show if patients treated with TABRECTA live longer or if their symptoms improve. There are ongoing studies to find out how TABRECTA works over a longer period of time.

It is not known if TABRECTA is safe and effective in children.

Important Safety Information
TABRECTA may cause serious side effects, such as lung or breathing problems. TABRECTA may cause inflammation of the lungs during treatment that may lead to death. Patients should be advised to contact their health care provider right away if they develop any new or worsening symptoms, including cough, fever, trouble breathing, or shortness of breath.

TABRECTA may cause abnormal blood test results, which may be a sign of liver problems. Patients should be advised that their health care provider will do blood tests to check their liver before starting and during treatment with TABRECTA. Patients should be advised to contact their health care provider right away if they develop any signs and symptoms of liver problems including the skin or the white part of their eyes turning yellow (jaundice), dark or "tea-colored" urine, light-colored stools (bowel movements), confusion, loss of appetite for several days or longer, nausea and vomiting, pain, aching, or tenderness on the right side of the stomach area (abdomen), or weakness or swelling in the stomach area.

The skin may be sensitive to the sun (photosensitivity) during treatment with TABRECTA. Patients should be advised to use sunscreen or wear clothes that cover their skin during treatment with TABRECTA to limit direct sunlight exposure.

For women of reproductive potential, TABRECTA can harm their unborn baby. They should use an effective method of birth control during treatment with TABRECTA and for 1 week after the last dose. Men who have partners who can become pregnant should use effective birth control during treatment with TABRECTA and for 1 week after the last dose.

Before taking TABRECTA, patients should tell their health care provider about all their medical conditions, including if they have or have had lung or breathing problems other than lung cancer, have or have had liver problems, or if they are pregnant or plan to become pregnant, as TABRECTA can harm their unborn babies. Females who are able to become pregnant should have a pregnancy test before they start treatment with TABRECTA and should use effective birth control during treatment and for 1 week after the last dose of TABRECTA. Patients should be advised to talk to their health care provider about birth control choices that might be right for them during this time and to tell their health care provider right away if they become pregnant or think they may be pregnant during treatment with TABRECTA. Males who have female partners who can become pregnant should use effective birth control during treatment and for 1 week after their last dose of TABRECTA.

Patients should tell their health care provider about all the medicines they take or start taking, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

The most common side effects of TABRECTA include swollen hands, ankles, or feet (peripheral edema); nausea and/or vomiting; tiredness and/or weakness (fatigue, asthenia); shortness of breath (dyspnea); loss of appetite; changes in bowel movements (diarrhea or constipation); cough; pain in the chest; fever (pyrexia); back pain; and decreased weight.

On June 4, 2021 SQZ Biotechnologies Company (NYSE: SQZ), focused on unlocking the full potential of cell therapies for multiple therapeutic areas, reported initial results from its ongoing Phase 1 clinical trial of SQZ-PBMC-HPV demonstrating that the investigational cell therapy is safe and well-tolerated and can stimulate immune responses in certain patients with advanced or metastatic Human Papillomavirus positive (HPV16+) tumors (Press release, SQZ Biotech, JUN 4, 2021, View Source [SID1234583582]). The trial also showed that the company’s clinical stage manufacturing process of its autologous cell therapy is fast and reliable. The monotherapy stage trial data of the company’s first Antigen Presenting Cell (APC) platform candidate was presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting; poster presentation 2536.

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"Our vision is to make cell therapies that are safe and available with rapid turnaround times, allowing access to patients who need them," said Oliver Rosen, M.D., chief medical officer at SQZ Biotechnologies. "The company’s first-in-human data of a cell-based therapeutic vaccine are encouraging and an important first step towards validation of our directed immunity approach. Within this small trial of patients with very advanced disease, four patients who had progressed after multiple prior therapies achieved stable disease. These early outcomes, combined with encouraging safety data and fast clinical-scale manufacturing times, support our plans to initiate the trial’s safety combination phase with immune checkpoint inhibitors."

Safety & Tolerability

A primary outcome measure in the monotherapy dose escalation phase of the trial is safety and tolerability. Findings from the trial show that SQZ-PBMC-HPV was safe and well-tolerated at all tested dose levels with patients receiving 2 to 10 doses. No dose-limiting toxicities were observed.

"Overall, SQZ-PBMC-HPV has been safe and well tolerated by patients, even advanced patients as we have seen in this study," said study author Antonio Jimeno, M.D., Ph.D., Professor of Medicine, Oncology and Otolaryngology, University of Colorado School of Medicine, and Co-Leader, Development Therapeutics Program, University of Colorado Cancer Center. "I look forward to completing the single agent portion of the trial and advancing into the combinations of SQZ-PBMC-HPV with immunotherapies."

There were no grade 3 or higher treatment related serious adverse events (SAEs). In one patient, a grade 2 cytokine release syndrome and immune-related reaction was observed. A related grade 3 adverse event (AE, anemia) was observed in another patient.

Manufacturability

Manufacturing feasibility is a secondary outcome measure in the monotherapy phase of the trial. All patient batches were produced under current good manufacturing practice regulations, met specifications, and yielded multiple cryopreserved doses in less than 24 hours.

The findings show that doses of SQZ-PBMC-HPV were released and available for administration approximately one week from the time a patient’s cells were drawn. Antigen presentation was confirmed in all patient batches independent of individual patient medical history or prognostic score.

Patient Characteristics & Immune Response Biomarkers

The clinical trial enrolled patients with HPV16+ cancers progressing after unlimited prior lines of therapy. The 12 enrolled patients had very advanced disease:

Median number of prior cancer treatments was four with one patient having received seven prior treatments
Eleven patients previously treated with an immune checkpoint inhibitor (ICI)
Six of the 12 patients had a Royal Marsden Hospital (RMH) score of 2. (RMH scores range from 0-to-3, with scores of 2 and higher predicting poor prognosis and short life expectancy)
Despite the treatment refractory status of the enrolled patients, 4 out of 6 patients with RMH scores less than 2, reflecting less advanced disease, achieved stable disease as best overall response. Two of these patients showed an increase in CD8 tumor infiltrating lymphocytes (TILs), an important biomarker in immune-oncology therapy development.

The study authors highlighted two patients – Patients 2 and 7 detailed below – which suggested that less advanced patients with lower tumor burden, such as patient two, might have a higher likelihood of clinical benefit.

Patient 2: Enrolled 3-and-half years after diagnosis and had a best overall response of progressive disease with ICI therapy. The patient had an RMH score of 1 and low tumor burden. She achieved stable disease while on the SQZ-PBMC-HPV-101 trial and remained on study for over 10 months. Image analysis of the central tumor 28 days after the first dose showed a 2-fold increase in CD8 TILs on treatment compared to baseline
Patient 7: Enrolled 1 year after diagnosis and had a partial response with chemotherapy in combination with ICI therapy but then progressed. He achieved stable disease after treatment on the SQZ-PBMC-HPV-101 trial and remained on study for three months. Image analysis of the central tumor showed a 6-fold increase in CD8 TILs on treatment compared to baseline
The company is now actively enrolling patients in the last monotherapy highest-dose cohort of the Phase 1 trial. These results will inform the dosage approach for the combination therapy phase of the clinical trial with immune checkpoint inhibitors.

Poster Presentation Details

Title: Initial Results of a first-in-human, dose escalation study of a cell-based vaccine in HLA-A* 02+ patients with recurrent, locally advanced or metastatic HPV16+ solid tumors
First Author: Antonio Jimeno, M.D., Ph.D., University of Colorado Cancer Center
Abstract Number: 2536
Poster Session: Developmental Therapeutics — Immunotherapy
Date and Time: A copy of the poster is available on-demand via the ASCO (Free ASCO Whitepaper) virtual meeting website.

SQZ-PBMC-HPV-101 Trial Design

SQZ-PBMC-HPV is being evaluated in a Phase 1 clinical trial for the treatment of HPV16+ advanced or metastatic solid tumors. Patients must be positive for the human leukocyte antigen serotype HLA-A*02. The investigational candidate, which targets E6 and E7 oncoproteins, is being studied as a monotherapy and in combination with immuno-oncology agents. The study’s primary outcome measures in the monotherapy and combination phases of the trial include safety and tolerability. Antitumor activity is a secondary outcome measure in both the monotherapy and combination stages of the trial, and manufacturing feasibility is a secondary outcome measure in the monotherapy phase of the trial. The monotherapy phase of the study includes escalating dose cohorts with a DLT window of 28 days and the definition of a recommended phase 2 dose. The planned safety combination phase of the study will include SQZ-PBMC-HPV and checkpoint inhibitors that have previously received regulatory approval. DLT will be measured over 42 days in the safety combination phase.

About Human Papillomavirus Positive Cancers

Human papillomavirus (HPV) is one of the most common viruses worldwide and certain strains persist for many years leading to cancer. According to the Centers for Disease Control (CDC), in the United States HPV+ tumors represent 3% of all cancers in women and 2% of all cancers in men, resulting in over 39,000 new cases of HPV+ tumors every year. HPV infection is larger outside of the U.S., and according to the International Journal of Cancer HPV+ tumors account for 4.5% of all cancers worldwide, resulting in approximately 630,000 new cases every year. According to the CDC, HPV infection plays a significant role in the formation of more than 90% of anal and cervical cancers, and most cases of vaginal (75%), oropharyngeal (70%), vulval (70%) and penile (60%) cancers.

On June 4, 2021 Kite, a Gilead Company (Nasdaq: GILD), reported that results from the primary analysis of ZUMA-3, a global, multicenter, single-arm, open-label Phase 1/2 study evaluating its chimeric antigen receptor (CAR) T-cell therapy Tecartus (brexucabtagene autoleucel) in adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) (Press release, Kite Pharma, JUN 4, 2021, View Source [SID1234583600]). The data were simultaneously published in The Lancet and presented during an oral session at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting from June 4 – 8 (Abstract #7002).

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"Outcomes in adults with acute lymphoblastic leukemia are poor relative to what is observed in children, with less than half of people over 20 years of age expected to survive the illness. It is on this background that CAR T-cell therapy with brexucabtagene autoleucel was tested in adults with relapsed B-ALL in ZUMA-3," said Bijal Shah, MD, ZUMA-3 investigator and medical oncologist, Moffitt Cancer Center, Tampa, Florida. "In this international, multicenter study, we observed a response rate of 71%. Importantly, the majority of these responses were associated with undetectable minimal residual disease."

In the pivotal Phase 2 portion of the trial, 71 patients with relapsed or refractory disease were enrolled. Among treated patients (n=55), 47% had received three or more prior therapies. At a median follow-up of 16.4 months, 71% of treated patients achieved a complete response (CR) or CR with incomplete hematological recovery (CRi), with 31% in ongoing response at data cut-off. 97% of those responders had deep molecular remission, with undetectable minimal residual disease (MRD), and median overall survival (OS) among all responders was not reached. Among 25 patients with prior blinatumomab treatment, the CR/CRi rate was 60%. Among all treated patients, median duration of response (DOR), relapse-free survival (RFS), and OS were 12.8 months, 11.6 months and 18.2 months, respectively.

Grade ≥3 adverse events occurred in 95% of patients, with anemia (49%) and pyrexia (36%) most frequently reported. Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in 24% and 25% of patients, respectively, and were generally reversed with treatment. Two Grade 5 treatment-related events occurred (one brain herniation and one case of septic shock).

Based on these data, the U.S. Food and Drug Administration (FDA) has accepted the supplemental Biologics License Application (sBLA) and granted Priority Review designation for Tecartus for the treatment of adult patients with relapsed or refractory B-cell precursor ALL, with a target action date under the Prescription Drug User Fee Act (PDUFA) of October 1, 2021. If approved, Tecartus would become the first and only CAR T-cell therapy approved for adults (≥18 years old) with relapsed or refractory ALL.

"The data presented at ASCO (Free ASCO Whitepaper) today validate the response rates seen in the Phase 1 portion of the ZUMA-3 study and the transformative potential of Tecartus in adult patients with ALL," said Frank Neumann, MD, PhD, Kite’s Global Head of Clinical Development. "We have already seen the impact of Tecartus for patients with relapsed or refractory mantle cell lymphoma, and these new data are a significant next step in our continued commitment in developing our therapies for patients with leukemias and lymphomas."

In 2016, Tecartus received Breakthrough Therapy Designation in recognition of the unmet medical need in adult patients with relapsed or refractory B-cell precursor ALL. Tecartus is currently approved for the treatment of relapsed or refractory mantle cell lymphoma, as the first and only CAR T-cell therapy to receive accelerated approval from the FDA in this indication. The Tecartus U.S. Prescribing Information has a Boxed Warning in its product label regarding the risks of cytokine release syndrome (CRS) and neurologic toxicities, and Tecartus is approved with a risk evaluation and mitigation strategy (REMS) due to these risks; see below for Indication and Important Safety Information.

Tecartus has not been approved by any regulatory agency for the treatment of adult patients with relapsed or refractory ALL. Its safety and efficacy are currently under review by the FDA for this indication.

About ALL
ALL is an aggressive type of blood cancer that can also involve the lymph nodes, spleen, liver, central nervous system and other organs. Approximately 1,030 adults are treated annually for relapsed or refractory ALL. Survival rates remain very poor in adult patients with relapsed or refractory ALL, with a median overall survival of approximately eight months with the most commonly used therapeutic agents.

B-cell precursor ALL is the most common form of the disease, accounting for approximately 75 percent of cases. Treatment for this form is typically associated with inferior outcomes compared with other types of ALL.

About ZUMA-3
ZUMA-3 is an ongoing international multicenter, registrational Phase 1/2 study in adult patients (≥18 years old) with ALL whose disease is refractory to or has relapsed following first standard systemic therapy with remission of 12 months or less, after two or more lines of systemic therapy or after allogeneic stem cell transplantation. The objectives of the study are to evaluate the safety and efficacy of Tecartus in this patient population.

About Tecartus
Tecartus is an autologous, anti-CD19 CAR T-cell therapy. Tecartus uses the XLP manufacturing process that includes T cell enrichment, a necessary step in certain B-cell malignancies in which circulating lymphoblasts are a common feature. In addition to adult ALL, Tecartus is also currently being evaluated in pediatric ALL. The use of Tecartus in both cancer types is investigational, and its safety and efficacy have not been established in these cancer types.

Tecartus Indication
Tecartus is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).

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

U.S. IMPORTANT SAFETY INFORMATION
BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including life-threatening reactions, occurred in patients receiving Tecartus. Do not administer Tecartus to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including life-threatening reactions, occurred in patients receiving Tecartus, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Tecartus. Provide supportive care and/or corticosteroids as needed.
Tecartus is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus REMS Program.
Cytokine Release Syndrome (CRS), including life-threatening reactions, occurred following treatment with Tecartus. In ZUMA-2, CRS occurred in 91% (75/82) of patients receiving Tecartus, including ≥ Grade 3 CRS in 18% of patients. Among the patients who died after receiving Tecartus, one had a fatal CRS event. The median time to onset of CRS was three days (range: 1 to 13 days) and the median duration of CRS was ten days (range: 1 to 50 days). Among patients with CRS, key manifestations (>10%) included fever (99%), hypotension (60%), hypoxia (37%), chills (33%), tachycardia (37%), headache (24%), fatigue (19%), nausea (13%), alanine aminotransferase increased (13%), aspartate aminotransferase increased (12%), and diarrhea (11%). Serious events associated with CRS included hypotension, fever, hypoxia, acute kidney injury, and tachycardia.

Ensure that a minimum of two doses of tocilizumab are available for each patient prior to infusion of Tecartus. Following infusion, monitor patients for signs and symptoms of CRS daily for at least seven days at the certified healthcare facility, and for four weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

Neurologic Toxicities, including those that were life-threatening, occurred following treatment with Tecartus. In ZUMA-2, neurologic events occurred in 81% of patients, 37% of whom experienced Grade ≥3 adverse reactions. The median time to onset for neurologic events was six days (range: 1 to 32 days). Neurologic events resolved for 52 out of 66 (79%) patients with a median duration of 21 days (range: 2 to 454 days). Three patients had ongoing neurologic events at the time of death, including one patient with serious encephalopathy. The remaining unresolved neurologic events were either Grade 1 or Grade 2. Fifty-four (66%) patients experienced CRS by the onset of neurological events. Five (6%) patients did not experience CRS with neurologic events and eight patients (10%) developed neurological events after the resolution of CRS. 85% of all treated patients experienced the first CRS or neurological event within the first seven days after Tecartus infusion.

The most common neurologic events (>10%) included encephalopathy (51%), headache (35%), tremor (38%), aphasia (23%), and delirium (16%). Serious events including encephalopathy, aphasia, and seizures occurred.

Monitor patients daily for at least seven days at the certified healthcare facility and for four weeks following infusion for signs and symptoms of neurologic toxicities and treat promptly.

REMS Program: Because of the risk of CRS and neurologic toxicities, Tecartus is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus REMS Program which requires that:

Healthcare facilities that dispense and administer Tecartus must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of two doses of tocilizumab are available for each patient for infusion within two hours after Tecartus infusion, if needed for treatment of CRS.
Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer Tecartus are trained in the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).
Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis, may occur due to dimethyl sulfoxide (DMSO) or residual gentamicin in Tecartus.

Severe Infections: Severe or life-threatening infections occurred in patients after Tecartus infusion. In ZUMA-2, infections (all grades) occurred in 56% of patients. Grade 3 or higher infections, including bacterial, viral, and fungal infections, occurred in 30% of patients. Tecartus should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 6% of patients after Tecartus infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

In immunosuppressed patients, including those who have received Tecartus, life-threatening and fatal opportunistic infections, including disseminated fungal infections (eg, candida sepsis and aspergillus infections) and viral reactivation (eg, human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Tecartus infusion. In ZUMA-2, Grade ≥3 cytopenias not resolved by Day 30 following Tecartus infusion occurred in 55% of patients and included thrombocytopenia (38%), neutropenia (37%), and anemia (17%). Monitor blood counts after infusion.

Hypogammaglobulinemia and B-cell aplasia can occur in patients receiving treatment with Tecartus. In ZUMA-2, hypogammaglobulinemia occurred in 16% of patients. Monitor immunoglobulin levels after treatment with Tecartus and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following Tecartus treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least six weeks prior to the start of lymphodepleting chemotherapy, during treatment, and until immune recovery following treatment with Tecartus.

Secondary Malignancies may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Tecartus infusion. Advise patients to refrain from driving and engaging in hazardous activities, such as operating heavy or potentially dangerous machinery, during this period.

Adverse Reactions: The most common adverse reactions (incidence ≥ 20%) were pyrexia, CRS, hypotension, encephalopathy, fatigue, tachycardia, arrhythmia, infection – pathogen unspecified, chills, hypoxia, cough, tremor, musculoskeletal pain, headache, nausea, edema, motor dysfunction, constipation, diarrhea, decreased appetite, dyspnea, rash, insomnia, pleural effusion, and aphasia. Serious adverse reactions occurred in 66% of patients. The most common serious adverse reactions (> 2%) were encephalopathy, pyrexia, infection – pathogen unspecified, CRS, hypoxia, aphasia, renal insufficiency, pleural effusion, respiratory failure, bacterial infections, dyspnea, fatigue, arrhythmia, tachycardia, and viral infections.

On June 4, 2021 Amgen (NASDAQ:AMGN) reported updated results for investigational bemarituzumab in combination with chemotherapy from the Phase 2 FIGHT trial (Press release, Amgen, JUN 4, 2021, View Source [SID1234583500]). The trial evaluated bemarituzumab plus chemotherapy (mFOLFOX6) versus chemotherapy alone in patients with FGFR2b-positive, HER2-negative frontline advanced gastric or gastroesophageal junction cancers (GEJ). New data includes median overall survival (OS), a secondary endpoint that was reached with longer follow-up, as well as additional analyses of patient subgroups.

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With a median follow-up of 12.5 months, the addition of bemarituzumab to chemotherapy resulted in a median OS of 19.2 months versus 13.5 months for chemotherapy alone in all randomized patients (n=155, HR: 0.6; 95% CI: 0.38, 0.94). In an exploratory pre-specified subgroup analysis, in patients with >10% of tumor cells overexpressing FGFR2b by immunohistochemistry (IHC), the median OS for bemarituzumab was 25.4 months versus 11.1 months (n=96, HR: 0.41; 95% CI: 0.23, 0.74).

The incidence of all grade adverse events was similar in the bemarituzumab plus chemotherapy and chemotherapy only arm of the study (100% versus 98.7%, respectively). The incidence of corneal adverse events was higher in the bemarituzumab plus chemotherapy arm versus the chemotherapy arm (all grade AEs 67.1% versus 10.4%), with dry eye reported as the most common corneal event (26.3%). The majority of the corneal adverse events were reversible.

The results were presented today in an oral presentation at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place virtually from June 4-8, 2021.

"Gastric cancer is the fourth leading cause of cancer death globally and 30% of frontline HER2-negative gastric cancer patients have tumors that overexpress FGFR2b," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "These updated results underscore the benefits that bemarituzumab plus chemotherapy may bring to patients who have been fighting this aggressive disease with chemotherapy alone. We now look forward to advancing bemarituzumab into Phase 3 development."

More than one million new gastric cancer cases are diagnosed annually, and gastric cancer is particularly prevalent in Asia.1,2 Approximately 80 to 85% of advanced gastric and GEJ cancers are HER2-negative, and approximately 30% of these tumors overexpress FGFR2b.3,4

"These updated results further validate our work on the role of FGFR2b overexpression in gastroesophageal cancer and demonstrate that treatment with bemarituzumab in combination with chemotherapy can deliver a clinically significant reduction in the risk of disease progression for patients whose tumors overexpress FGFR2b," said Daniel V.T. Catenacci, MD, PhD, medical oncologist and principal investigator at the University of Chicago.

In April 2021, bemarituzumab was granted Breakthrough Therapy Designation by the U.S. FDA based upon a subset of patients from the FIGHT trial who showed at least 10% of tumor cells overexpressing FGFR2b. Amgen continues to investigate the role of FGFR2b and will continue to work with regulatory agencies on next steps, including Phase 3 development, to bring this potential first-in-class therapy to patients.

About Bemarituzumab
Bemarituzumab (anti-FGFR2b) is a Phase 3 ready, potential first-in-class, investigational targeted antibody that is designed to block specific fibroblast growth factors (FGFs) from binding and activating FGFR2b, inhibiting several downstream pro-tumor signaling pathways and potentially slowing cancer progression. Bemarituzumab is being developed in gastric and GEJ cancer as a targeted therapy for tumors that overexpress FGFR2b. The company is also evaluating the potential for bemarituzumab in other cancers that overexpress FGFR2b.

Zai Lab (Shanghai) Co. Ltd. was granted an exclusive license to develop and commercialize bemarituzumab in Greater China, and Zai Lab collaborated with Five Prime on the Phase 2 FIGHT trial in Greater China.

About FIGHT
The FIGHT trial evaluated bemarituzumab plus chemotherapy (mFOLFOX6) versus chemotherapy alone in patients with FGFR2b-positive, HER2-negative frontline advanced gastric or GEJ cancer. In the study, treatment with bemarituzumab plus chemotherapy demonstrated clinically significant and substantial improvements in the primary endpoint of progression-free survival (PFS) and secondary endpoint of overall survival (OS) in the patient population in which at least 10% of tumor cells overexpressed FGFR2b. Additional analysis showed a positive correlation between benefit and the prevalence of FGFR2b+ tumor cells, affirming both the importance of the FGFR2b target and the activity of bemarituzumab against this target. The Breakthrough Therapy Designation was granted based upon this subset of patients who showed at least 10% of tumor cells overexpressing FGFR2b.

About Amgen Oncology
At Amgen Oncology, our mission to serve patients drives all that we do. That’s why we’re relentlessly focused on accelerating the delivery of medicines that have the potential to empower all angles of care and transform lives of people with cancer.

For the last four decades, we have been dedicated to discovering the firsts that matter in oncology and to finding ways to reduce the burden of cancer. Building on our heritage, Amgen continues to advance the largest pipeline in the Company’s history, moving with great speed to advance those innovations for the patients who need them.

At Amgen, we’re advancing oncology at the speed of life.