On September 17, 2021 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of Gavreto (pralsetinib) as a monotherapy for the treatment of adult patients with rearranged during transfection (RET) fusion-positive advanced non-small cell lung cancer (NSCLC) not previously treated with a RET inhibitor (Press release, Hoffmann-La Roche, SEP 17, 2021, View Source [SID1234587883]).

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"This positive CHMP opinion for Gavreto represents another important step towards our goal of providing effective therapeutics that target genomic drivers of disease for as many cancer patients as possible," said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. "Advances in personalised medicine also underscore the importance of tumour genomic profiling to identify patients who may benefit from targeted therapies."

RET alterations are key disease drivers in many cancer types, including NSCLC and multiple types of thyroid cancer. RET fusion-positive NSCLC affects approximately 37,500 people worldwide each year and the disease often affects those who least expect it;[1,2,3] RET fusion-positive NSCLC is often identified in younger people with a minimal to no history of smoking.[3] These cancers also typically represent a high unmet need, due to limitations associated with standard therapies.[4,5,6] Biomarker testing for these fusions is the most effective way to identify people with advanced NSCLC who are eligible for treatment with Gavreto. Gavreto is a highly selective, potent, and CNS-penetrant RET inhibitor and, together with Alecensa (alectinib) and Rozlytrek (entrectinib), is part of Roche’s portfolio of targeted treatments for NSCLC. Together, they offer personalised treatment options for almost one in ten people with advanced NSCLC.[7]

The CHMP recommendation is based on the results of the phase I/II ARROW study, in which Gavreto demonstrated rapid, potent, and durable clinical activity in patients with advanced RET fusion-positive NSCLC.[8] A final decision regarding the approval of Gavreto is expected from the European Commission in the coming months.

Gavreto has also shown activity across multiple solid tumour types, reflecting tumour-agnostic potential.[9] In September 2020, the U.S. Food and Drug Administration (FDA) approved Gavreto for the treatment of adults with metastatic RET fusion-positive NSCLC, and in December 2020 it was approved for the treatment of adult and paediatric patients 12 years of age and older with advanced RET-altered thyroid cancers. Gavreto has since been approved in Canada, mainland China and Switzerland. In the European Union, the MAA for Gavreto for the treatment of adults with RET fusion-positive NSCLC is ongoing, and a submission for RET-altered thyroid cancers is planned. Regulatory submissions for these indications are underway in multiple countries worldwide.

Blueprint Medicines and Roche are co-developing Gavreto globally, with the exception of certain territories in Asia, including China.* Blueprint Medicines and Genentech, a wholly owned member of the Roche Group, are commercialising Gavreto in the US and Roche has exclusive commercialisation rights for Gavreto outside of the US, with the exception of certain territories in Asia, including China.*

*CStone Pharmaceuticals retains all rights to the development and commercialisation of Gavreto in these territories under its existing collaboration with Blueprint Medicines.

About the ARROW study[10]
ARROW is an ongoing phase I/II, open-label, first-in-human study designed to evaluate the safety, tolerability and efficacy of Gavreto, administered orally in people with rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), RET-mutant medullary thyroid cancer, RET fusion-positive thyroid cancer and other RET-altered solid tumours. ARROW is being conducted at multiple sites across the United States, Europe and Asia.

An update from the ARROW study was presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2021 Virtual Scientific Programme, 4-8 June.[11] In 126 patients with RET fusion-positive NSCLC who previously received platinum-based chemotherapy, Gavreto demonstrated an overall response rate (ORR) of 62% (95% CI: 53%, 70%), a clinical benefit rate (CBR) of 74% (95% CI: 65%, 81%), and a disease control rate (DCR) of 91% (95% CI: 85%, 96%). Median progression-free survival (PFS) was 16.5 months (95% CI: 10.5 months, 24.1 months). In 68 treatment-naïve patients, the confirmed ORR was 79% (95% CI: 68%, 88%), the CBR was 82% (95% CI: 71%, 91%), and the DCR was 93% (95% CI: 84%, 98%). Median PFS was 13.0 months (95% CI: 9.1 months, not reached (NR)). In 25 treatment-naïve patients who were enrolled after eligibility criteria were revised, to allow candidates for platinum-based therapy, the confirmed ORR was 88% (95% CI: 69%, 98%), the CBR was 88% (95% CI: 69%, 98%), and the DCR was 96% (95% CI: 80%, 100%). Median PFS was not reached. In addition, Gavreto was well-tolerated; of the 471 ARROW trial patients across RET-altered tumour types, the most common (≥ 25%) treatment-related adverse events were neutropenia, increased liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), anaemia, white blood cell count decrease, high blood pressure (hypertension) and lack of energy (asthenia).

About rearranged during transfection (RET)-altered cancers
RET gene alterations, such as fusions and mutations, are key disease drivers in many types of cancer, including non-small cell lung cancer (NSCLC) and several types of thyroid cancers. There are approximately 2.21 million cases of lung cancer diagnosed each year worldwide,[1] of which approximately 1.8 million are NSCLC and RET fusions are present in approximately 1-2% of these patients,[2,3] meaning RET fusion-positive NSCLC affects up to 37,500 people each year. Additionally, approximately 10-20% of people with papillary thyroid cancer (the most common type of thyroid cancer) have RET fusion-positive tumours,[12] and roughly 90% of people with advanced medullary thyroid cancer (a rare form of thyroid cancer) carry RET mutations.[13] Oncogenic RET fusions also are observed at low frequencies in cholangiocarcinoma, colorectal, neuroendocrine, ovarian, pancreatic and thymus cancers.

About Gavreto (pralsetinib)
Gavreto is a once-daily, oral targeted treatment designed to selectively target rearranged during transfection (RET) alterations, including fusions and mutations, regardless of the tissue of origin. Preclinical data have shown that Gavreto inhibits primary RET fusions and mutations that cause cancer in subsets of patients, as well as secondary RET mutations predicted to drive resistance to treatment. Blueprint Medicines and Roche are co-developing Gavreto for the treatment of people with various types of RET-altered cancers.

About Roche in lung cancer
Lung cancer is a major area of focus and investment for Roche, and we are committed to developing new approaches, medicines and tests that can help people with this deadly disease. Our goal is to provide an effective treatment option for every person diagnosed with lung cancer. We currently have six approved medicines to treat certain kinds of lung cancer and more than ten medicines being developed to target the most common genetic drivers of lung cancer or to boost the immune system to combat the disease.

On September 17, 2021 Novartis reported important findings from a real-world study evaluating the safety and efficacy of alpelisib for people living with PIK3CA-Related Overgrowth Spectrum (PROS) who received treatment daily for at least 24 weeks. Results from EPIK-P1 showed alpelisib effectively reduced volume of clinically significant PROS-related lesions and improved signs and symptoms in pediatric and adult patients (Press release, Novartis, SEP 17, 2021, View Source [SID1234587900]). Results were presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2021 [LBA23].

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"There are few options available to manage PROS conditions, and they are mainly focused on addressing worsening symptoms. It is devastating for patients to be without treatments that address the underlying cause of PROS," said Guillaume Canaud, MD, PhD, Necker-Enfants Malades Hospital – AP-HP, the Paris Descartes University, Inserm (INEM Institute Necker Enfants Malades – Centre for Molecular Medicine). "The EPIK-P1 findings show robust clinical benefit for adult and pediatric patients and a potential new path forward for those impacted by PROS conditions."

In EPIK-P1, alpelisib reduced target lesion volume and improved PROS-related symptoms and manifestations. The primary endpoint analysis conducted at week 24 in patients with complete cases (n=32) showed 38% of patients achieving a response to treatment which was defined as 20% or greater reduction in the sum of PROS target lesion volume. Nearly three in four patients (74%) showed some reduction in target lesion volume, with a mean reduction of 13.7%, and no patients experienced disease progression at time of primary analysis.

Additionally, at week 24, investigators reported patient improvements from baseline in pain (90%), fatigue (76%), vascular malformation (79%), limb asymmetry (69%), and disseminated intravascular coagulation (55%) across the full study population (n=57).

"Thanks to the data from patients and physicians included in the analysis of EPIK-P1, we have findings to help validate the potential of alpelisib in PROS and have taken an important step toward reimagining medicine for the PROS community," said Jeff Legos, Executive Vice President, Global Head of Oncology & Hematology Development. "We will continue to discuss this real-world evidence with the FDA in an effort to bring this treatment to people in need as quickly as possible."

Adverse events (AEs) and treatment-related AEs (TRAEs) were experienced by 83% and 39% of patients, respectively. Most AEs were mild to moderate in severity, and there were no AEs leading to treatment discontinuation. The most common AEs of any grade were diarrhea (16%), hyperglycemia (12%), aphthous ulcers (11%), and stomatitis (5%). The most common grade 3/4 AE was cellulitis (4%); one adult case was considered treatment-related.

PROS is a wide-ranging spectrum of disorders caused by a mutation in the PIK3CA gene. PROS conditions are rare and visually diverse, and are typically characterized by atypical growths and anomalies in blood vessels, the lymphatic system and other tissues. PROS conditions can look different from each other in size, shape, and type of growth or malformation based on where in the body the mutation is found.1,2 PROS can disrupt mobility and cognitive function in some patients and may lead to life-threatening complications.3-5

There are no approved medical therapies for PROS conditions. PROS management varies by patient, and surgery and radiologic embolization are common with patients often undergoing multiple procedures due to frequent regrowth following surgery.1,3,4,6-9 There is a significant need for treatment options for PROS that reduce overgrowth, address symptoms, and improve quality of life.3,9-10

The U.S. Food and Drug Administration (FDA) granted alpelisib Breakthrough Therapy Designation on November 13, 2019, and discussions with FDA about alpelisib for PROS are ongoing.

About PIK3CA-Related Overgrowth Spectrum (PROS)
The PROS classification was proposed at the National Institutes of Health in a workshop in 2013 to unite a group of rare overgrowth conditions caused by PIK3CA mutations.1,2 Specific conditions associated with PROS include KTS, CLOVES syndrome, ILM, MCAP/M–CM, HME, HHML, FIL, FAVA, macrodactyly, muscular HH, FAO, CLAPO syndrome and epidermal nevus, benign lichenoid keratosis, or seborrheic keratosis.1,2 The estimated prevalence of PROS conditions is approximately 14 people per million.6 To learn more, visit understandingpros.com.

About EPIK-P1
EPIK-P1 is a global, site-based retrospective non-interventional medical chart review of pediatric and adult male and female patients aged 2 years or older with PIK3CA-Related Overgrowth Spectrum (PROS) who received alpelisib via a compassionate use program. Primary endpoint is proportion of patients with response at 24 weeks, defined as achieving at least 20% reduction from index date in the sum of measurable target lesion volume via central imaging. Data were obtained from medical charts of 57 patients (39 pediatric, 18 adult) at seven sites in five countries. There were 32 complete cases, meaning there were complete scans for comparison at baseline and date of analysis, and one patient discontinued prior to week 24 due to lack of clinical efficacy.

Alpelisib is not approved by any regulatory authority for the treatment of PROS conditions.

On September 17, 2021, AIM ImmunoTech Inc. (the "Company") reported a Company Presentation On September 17, 2021, AIM ImmunoTech Inc. (the "Company") posted a Company Presentation

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On September 17, 2021 Protagonist Therapeutics, Inc. (Nasdaq: PTGX) ("Protagonist" or "the Company") reported the receipt of a verbal communication from the U.S. Food and Drug Administration (FDA) that Protagonist’s clinical studies for rusfertide, an investigational product candidate currently in development, have been placed on a clinical hold (Press release, Protagonist, SEP 17, 2021, View Source [SID1234587885]).

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The clinical hold follows Protagonist’s notification to the FDA of a recent non-clinical finding in a 26-week rasH2 transgenic mouse model study. The rasH2 model is designed to detect signals related to tumorigenicity, and benign and malignant subcutaneous skin tumors were observed in this study.

The Company is working with the FDA and will be prepared to make all appropriate updates to clinical study documents and determine the next steps in consultation with the FDA. In particular, we will provide additional clinical safety reports, update the investigator brochures and patient informed consent forms, and make necessary modifications to study protocols. Dosing of patients in all ongoing clinical trials with rusfertide will be put on hold, and study investigators have been contacted to facilitate patient notification.

"Patient safety is our absolute top priority," said Dinesh Patel, President and Chief Executive Officer of Protagonist. "We are fully committed to working closely with the FDA in understanding and evaluating potential clinical risks and determining next steps for the development of rusfertide."

On September 17, 2021 ImCheck Therapeutics reported that data at the ESMO (Free ESMO Whitepaper) Congress 2021 from its ongoing EVICTION Phase I/IIa clinical trial with its lead antibody ICT01showing anti-tumor immune responses, resulting in increased tumor infiltration and disease control in patients with a variety of relapsed/refractory solid tumors (Press release, ImCheck Therapeutics, SEP 17, 2021, View Source [SID1234587901]). The presentation includes the first data from the trial’s combination cohort of ICT01 plus pembrolizumab in patients who progressed on at least one prior checkpoint inhibitor regimen. Five of the six enrolled patients in the first two dose cohorts were evaluable for efficacy at week eight or beyond. Three of four patients receiving 2 mg ICT01 plus 200 mg pembrolizumab every three weeks (cohort two) achieved disease control: two patients (bladder cancer, metastatic melanoma) showed partial responses and one patient (non-small cell lung cancer) showed stable disease at week 16 or beyond, according to RECIST1.1. Although preliminary, these data provide the first demonstration of clinical responses that are consistent with the observed coordinated antitumor immune response of the innate (γ9δ2 T cells) and adaptive (CD8 T cells) immune systems following ICT01 treatment.

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The data were included in an oral presentation (958O) by Aurélien Marabelle, MD, PhD, Lead Investigator for EVICTION, titled: "Coordinated Activation of Antitumor Responses of γ9δ2 and CD8 T Cells by Targeting BTN3A with ICT01 in Patients with Solid Tumors: EVICTION Trial," on September 17, 2021, from 1:50 – 2:00 pm CET in the Proffered Paper session – Investigational Immunotherapy.

"These data are exciting as they demonstrate for the first time tumor responses in patients treated with ICT01, which continues to support the previously observed immune system activation and good safety profile," commented Aurélien Marabelle, MD, PhD, Immuno-Oncologist at Gustave Roussy, Villejuif, France and Lead Investigator for EVICTION. "Patients in this study are heavily pre-treated, including prior checkpoint inhibitor therapy, and at the stage they join the EVICTION trial have no available standard-of-care treatment options. These preliminary signs of disease control are encouraging and, therefore, we are looking forward to additional data readouts from the EVICTION trial."

"Our anti-BTN3A antibody, ICT01, has already shown promising anti-tumor immune activation and responses so we are cautiously optimistic when reporting today’s preliminary signs of disease control in three patients, including a reduction in tumor burden of up to [~]50% in two of those patients," said Paul Frohna, MD, PhD, Chief Medical Officer at ImCheck Therapeutics. "We remain on target to present additional EVICTION trial data later this year. On behalf of all of us at ImCheck, I want to thank the patients and their families, and the investigators and their clinical study teams for contributing to our study."

The ongoing EVICTION trial is evaluating ICT01 in patients with advanced relapsed/refractory solid and hematologic cancers who have no remaining standard of care treatment options. The presentation today covers results from a dose escalation cohort of evaluable patients with solid tumors (n=32) receiving ICT01 monotherapy and two dose cohorts of evaluable patients with solid tumors (n=6) who previously failed at least one checkpoint inhibitor regimen that were treated with ICT01 in combination with pembrolizumab.

The data from patients with solid tumors treated with ICT01 monotherapy demonstrated a dose-dependent target occupancy of ICT01 binding to BTN3A on T cells that induced a dose-dependent migration of γ9δ2 T cells out of the circulation. Increases in serum TNFα and IFNγ were observed within minutes to hours at doses ≥ 2 mg ICT01 that appear to positively correlate with ICT01 dose, the baseline γ9δ2 T cell counts, and the activation and migration of NK and CD8+ T cells from the circulation. Tumor biopsies showed infiltration of γδ, CD3+ and CD8+ T cells in patients with immune desert at baseline demonstrating the ability to remodel the tumor immune microenvironment across a range of tumor phenotypes. Across the two cohorts treated with a combination of ICT01 and pembrolizumab, preliminary signs of tumor regression were observed at 2 mg ICT01 in two patients. These data may reflect the contribution of ICT01-activated γ9δ2 T cells to remodel the tumor immune microenvironment and increase tumor infiltration of CD8+ T cells, which can be activated by an anti-PD-1 agent like pembrolizumab.

Following multiple safety reviews by the independent Safety Review Committee, the EVICTION trial is continuing further dose escalation in the hematologic monotherapy and combination therapy arms of the study. Part 2 for the monotherapy expansion cohorts is expected to begin enrolling second- and third-line treated patients with ovarian (Group D) or head and neck squamous cell carcinomas (Group E) in Q4 2021. In addition to good preliminary safety, tolerability and immune response data, new results presented at this conference indicate for the first time a beneficial clinical response with signs of tumor shrinkage.

The ESMO (Free ESMO Whitepaper) presentation slides will be available on ImCheck’s corporate website directly following the presentation.

About the EVICTION Trial
EVICTION is a first-in-human, dose escalation (Part 1) and cohort expansion (Part 2) clinical trial of ICT01 in patients with various advanced relapsed or refractory solid or hematologic cancers that have exhausted standard of care treatment options. Part 1 is a basket trial designed to characterize the preliminary safety, tolerability, and pharmacodynamic activity of ICT01 as monotherapy (Group A: solid tumors; Group B: hematologic tumors) and in combination with pembrolizumab (Group C: solid tumors). Group A includes bladder, breast, colorectal, gastric, melanoma, ovarian, prostate, and pancreatic cancer patients, Group B includes acute myeloid leukemia, acute lymphocytic leukemia, follicular lymphoma, and diffuse large B cell lymphoma patients, and Group C includes bladder, head and neck squamous cell carcinoma, melanoma, and non-small cell lung cancer patients. Basket trials are a clinical trial design that allows new drugs to be tested rapidly in a range of indications, providing initial data on multiple parameters that can contribute to an accelerated development timeline. More information on the EVICTION trial can be found at clinicaltrials.gov (NCT04243499).

About ICT01
ICT01 is a humanized, anti-BTN3A (also known as CD277) monoclonal antibody that selectively activates γ9δ2 T cells, which are part of the innate immune system that is responsible for immunosurveillance of malignancy and infections. The 3 isoforms of BTN3A targeted by ICT01 are overexpressed on a number of solid tumors (e.g., bladder, colorectal, melanoma, ovarian, pancreatic, lung) and hematologic cancers (e.g., leukemia & lymphoma) and also expressed on the surface of innate (e.g., γδ T cells and NK cells) and adaptive immune cells (T cells and B cells). BTN3A is essential for the activation of the anti-tumor immune response of γ9δ2 T cells.

As demonstrated in EVICTION data presented at AACR (Free AACR Whitepaper), ICT01 selectively activates circulating γ9δ2 T cells that leads to migration of γ9δ2 T cells out of the circulation and into target tissue (e.g., tumors), while also activating the tumor-resident γ9δ2 T cells to directly kill malignant cells, which is accompanied by secretion of two key inflammatory cytokines, IFNg and TNFa, that contribute to the expansion of the anti-tumor immune response. ICT01 has been shown to have anti-tumor activity against a range of cancers in in vitro and in vivo tumor models.