On April 4, 2024 Astrazeneca reported that positive high-level results of the ADRIATIC Phase III trial showed Imfinzi (durvalumab) demonstrated a statistically significant and clinically meaningful improvement in the dual primary endpoints of overall survival (OS) and progression-free survival (PFS) in patients with limited-stage small cell lung cancer (LS-SCLC) who had not progressed following concurrent chemoradiotherapy (cCRT) compared to placebo after cCRT (Press release, AstraZeneca, APR 4, 2024, View Source [SID1234641792]).

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Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer that typically recurs and progresses rapidly despite initial response to chemotherapy and radiotherapy in LS-SCLC patients.1,2 The prognosis is particularly poor for LS-SCLC, as only 15-30% of these patients will be alive five years after diagnosis.3

Suresh Senan, PhD, Professor of Clinical Experimental Radiotherapy at the Amsterdam University Medical Center, The Netherlands, and principal investigator in the trial said: "Many patients treated for limited-stage small cell lung cancer face disease recurrence and the standard of care has remained unchanged for decades. ADRIATIC is the first global Phase III immunotherapy trial to deliver significant, clinically meaningful improvement in survival in this setting, marking a breakthrough for patients with this devastating disease."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "These exciting results build on the transformative efficacy of Imfinzi in extensive-stage small cell lung cancer and demonstrate the potential to bring a curative-intent immunotherapy treatment to this earlier-stage setting of small cell lung cancer for the first time. These data, together with the PACIFIC data in unresectable, Stage III non-small cell lung cancer, underscore the pioneering role of Imfinzi in the treatment of early lung cancer following chemoradiotherapy."

The safety profile for Imfinzi was consistent with its known profile, and no new safety signals were identified.

These data will be presented at a forthcoming medical meeting and shared with global regulatory authorities.

The second experimental arm testing the efficacy of Imjudo (tremelimumab) added to Imfinzi as a secondary endpoint remains blinded and will continue to the next planned analysis.

Imfinzi is approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage SCLC (ES-SCLC) based on the CASPIAN Phase III trial. Imfinzi is also the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after CRT based on the PACIFIC Phase III trial.

Notes:

Small cell lung cancer
Lung cancer is the leading cause of cancer death among men and women and accounts for about one-fifth of all cancer deaths.4 Lung cancer is broadly split into NSCLC and SCLC, with about 15% of cases classified as SCLC.5

LS-SCLC (Stage I-III) is classified as SCLC that is generally only in one lung or one side of the chest.6 LS-SCLC accounts for approximately 30% of SCLC diagnoses and the prognosis remains poor despite curative-intent treatment with standard-of-care cCRT.7

ADRIATIC
The ADRIATIC trial is a randomised, double-blind, placebo-controlled, multi-centre global Phase III trial evaluating Imfinzi monotherapy and Imfinzi plus Imjudo versus placebo in the treatment of 730 patients with LS-SCLC who had not progressed following cCRT. In the experimental arms, patients were randomised to receive a 1500mg fixed dose of Imfinzi with or without Imjudo 75mg every four weeks for up to four doses/cycles each, followed by Imfinzi every four weeks for up to 24 months.

The dual primary endpoints are PFS and OS for Imfinzi monotherapy versus placebo. Key secondary endpoints included OS and PFS for Imfinzi plus Imjudo versus placebo, safety and quality of life measures. The trial includes 164 centres in 19 countries across North and South America, Europe and Asia.

Imfinzi 
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

In addition to its indications in unresectable, Stage III NSCLC and ES-SCLC, Imfinzi is currently approved in a number of countries in combination with a short course of Imjudo and chemotherapy for the treatment of metastatic NSCLC.

Imfinzi is also approved in a number of countries in combination with chemotherapy in locally advanced or metastatic biliary tract cancer and in combination with Imjudo in unresectable hepatocellular carcinoma (HCC). Imfinzi is also approved as a monotherapy in unresectable HCC in Japan and the EU and in previously treated patients with advanced bladder cancer in a small number of countries.

Since the first approval in May 2017, more than 220,000 patients have been treated with Imfinzi. As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, breast cancer, several gastrointestinal cancers and other solid tumours.

Imjudo
Imjudo (tremelimumab) is a human monoclonal antibody that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Imjudo blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death.

In addition to its approved indications in combination with Imfinzi in liver and lung cancers, the combination of Imjudo and Imfinzi is being evaluated across multiple tumour types including locoregional HCC (EMERALD-3) and bladder cancer (VOLGA and NILE).

On April 4, 2024 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage biotechnology company developing first-in-classi targeted and immune-mediated therapeutics to fight cancer, reported that Cancer Research Communications published positive clinical data from the dose-escalation Phase 1 trial of TPST-1120 in an article titled "First-in-Human Phase I Trial of TPST-1120, an inhibitor of PPARα, as Monotherapy or in Combination with Nivolumab, in Patients with Advanced Solid Tumors (Press release, Tempest Therapeutics, APR 4, 2024, View Source [SID1234641791])." The data showed that TPST-1120 demonstrated clinical activity, including tumor shrinkage, even in PD-1 inhibitor refractory and immune compromised cancers, and was well tolerated both as monotherapy and in combination with nivolumab. These earlier Phase 1 data complement the positive Phase 1b/2 data reported in October 2023 from a global randomized study of TPST-1120 in combination with atezolizumab and bevacizumab in first-line patients with advanced HCC, which showed clinical superiority of the TPST-1120 arm across multiple study endpoints and relevant biomarker-defined patient subpopulations.

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"In this Phase 1 study of TPST-1120, we saw the first evidence of anti-tumor activity in multiple cancer types, affirming our belief that PPARα inhibition is an exciting and novel approach for cancer treatment," said Sam Whiting, M.D., Ph.D., chief medical officer and head of R&D at Tempest. "These early-phase data are supported by the positive top line results of the ongoing randomized Phase 1b/2 trial in first-line HCC. We believe there is tremendous potential for TPST-1120 to make a meaningful impact for patients and we look forward to providing updated data this year."

About the TPST-1120 Phase 1 Study

In this first-in-human Phase 1 study, 35 patients were treated with escalating doses of TPST-1120 either as monotherapy (20 patients) or in combination with the anti-PD-1 therapy, nivolumab (15 patients). TPST-1120 was well-tolerated as monotherapy and in combination, with a maximum tolerated dose not identified and predominantly low-grade toxicity. Notwithstanding the late-line stage of these patients and difficult to treat tumor types, clinical benefit was observed as both a monotherapy and combination.2 In monotherapy, a best response of stable disease (SD) was observed in 53% (10/19) of evaluable patients, with 5 of those patients staying on treatment for more than 5 months. Tumor shrinkage of target lesions on treatment occurred in 21% (4 patients) and a best response of no target lesion growth was seen in 3 additional patients.

In the combination therapy cohorts, including patients with heavily pretreated cholangiocarcinoma (CCA), hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC), the objective response rate (ORR) was 23% (3/13, all partial responses, or PRs) across all dose levels and 30% (3/10) at the two highest dose levels of TPST-1120, suggesting dose-responsive anti-cancer activity. These responses included a 50% ORR in patients with RCC (2/4 evaluable) who had previously progressed on anti-PD-1 therapy, and one patient with heavily pre-treated CCA. Analysis of whole blood specimens revealed changes in expression of PPARα-associated immune genes that were related to TPST-1120 dose levels. Some of these changes were only observed in patients who had partial responses, linking TPST-1120 biological activity to clinical outcome.

About TPST-1120

TPST-1120 is an oral, small molecule, selective PPAR⍺ antagonist. Tempest’s data suggest that TPST-1120 treats cancer by targeting tumor cells directly and by modulating immune suppressive cells and angiogenesis in the tumor microenvironment. In an ongoing global randomized phase 1b/2 study of TPST-1120 in combination with atezolizumab and bevacizumab in first-line patients with advanced HCC, the TPST-1120 arm showed clinical superiority across multiple study endpoints when compared to atezolizumab and bevacizumab alone, the standard of care. These randomized data were supported by positive results observed in the Phase 1 clinical trial in patients with heavily pretreated advanced solid tumors. TPST-1120 is wholly-owned by Tempest.

On April 4, 2024 TC BioPharm (Holdings) PLC ("TC BioPharm" or the "Company") (NASDAQ: TCBP) a clinical stage biotechnology company developing platform allogeneic gamma-delta T cell therapies for cancer and other indications, reported the execution of a non-binding letter of intent as part of its M&A strategy aimed at expanding its therapeutic platform and leveraging NK (natural killer) cells in treating both solid tumors and other indications (Press release, TC Biopharm, APR 4, 2024, View Source [SID1234641790]).

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The target asset acquisition covers the proprietary manufacturing process of two allogeneic CAR-NK therapeutics, both of which TCB believes are valuable as monotherapies as well as in conjunction with TCB-008 in the future. Initially, the CAR platforms both are targeted towards solid tumors, including a CD-70 CAR NK technology and an HER2 CAR-NK technology. TCB sees substantial synergies in this potential acquisition, both in clinical therapeutic terms of TCB-008 in combination with the CAR-NK assets, as well as leveraging the existing expertise and human capital of TCB to further advance and refine the manufacturing process while bringing in additional CAR expertise to advance multiple platforms.

There is substantial evidence supporting the rationale that gamma delta t-cells and NK cells play important and symbiotic roles in the immune response for various disease indications. Due to the fact that NK cells do not need to be genetically engineered in order to recognize cancer cells, patients are able to be treated in an expedited timeframe.

Under the terms of the LOI, TC BioPharm has been granted exclusivity while the parties work in good faith on the drafting of a definitive agreement. There can be no assurance that a definitive agreement will be executed or that the proposed transaction will be consummated on the terms or timeframe currently contemplated. TC BioPharm’s Board of Directors’ approval and disclosed thereafter. Upon execution of the definitive agreements, the completion of the transaction will be subject to, among other matters, satisfaction of the conditions negotiated therein, the Company having secured adequate financing, and receipt of all third party (including governmental) approvals, licenses, consents, and clearances, as and when applicable. There can be no assurance that the Proposed Transaction will be completed on the terms contemplated in the LOI or otherwise.

"With the difficult times in cell therapy we see this as a unique opportunity to aggressively expand our asset base in other immune cells and immune responder technologies, which we believe will further enhance TCBP as a leader in cell therapy and increase our future value," said Mr. Bryan Kobel, CEO of TC BioPharm. "We believe this proposed asset acquisition brings not just a new and expanded opportunity in cancer, but synergies in combination efforts with TCB-008 in numerous indications. This proposed asset acquisition would leverage our strengths in optimizing manufacturing processes and developing new cell therapies rapidly to the clinical stage, as well as our core asset on asset base expansion and combination efforts with TCB-008. By merging complimentary technologies under one roof we believe the potential exit value of TCBP is increased, patients will benefit in expanded clinical trial efforts which we will control, and ultimately benefit shareholders in future value."

On April 4, 2024 Sensei Biotherapeutics, Inc. (Nasdaq: SNSE), a clinical stage immuno-oncology company focused on the discovery and development of next-generation therapeutics for cancer patients, reported the publication of a peer-reviewed research paper in Nature Communications (Press release, Sensei Biotherapeutics, APR 4, 2024, View Source [SID1234641789]). The research was conducted by scientists at Sensei Biotherapeutics in collaboration with genOway and the laboratory of Dr. Robert Schreiber at the Washington University, St. Louis School of Medicine.

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The paper describes Sensei Biotherapeutics’ approach to the discovery and development of SNS-101, which was designed to potently and selectively target the active protonated form of VISTA, a protein that plays a significant role in suppressing T-cell activation. VISTA was previously considered undruggable due to its extensive expression on myeloid cells, leading to safety issues such as cytokine release syndrome (CRS), in addition to a pharmacokinetic sink, which poses a significant challenge in reaching therapeutically relevant concentrations. The paper details the mechanism and characteristics of SNS-101, a novel pH-sensitive monoclonal antibody. SNS-101 was shown to bind to a novel epitope of VISTA that is remodeled under low pH conditions, switching VISTA into an active state that engenders extensive T-cell suppression. SNS-101 is designed to block VISTA by inhibiting its interaction with PSGL-1 on T-cells resulting in T-cell activation. Subsequently, in various preclinical models, SNS-101 was shown to mitigate CRS risk and maintain a favorable pharmacokinetic and safety profile, all of which had thwarted the clinical development of first generation, non-pH sensitive anti-VISTA antibodies.

"The publication of this research in Nature Communications serves as important validation for our tumor-targeting approach and confirms our ability to design highly selective antibodies that target VISTA under the unique conditions of the tumor microenvironment," said Edward van der Horst, Ph.D., Chief Scientific Officer of Sensei Bio. "Our studies of SNS-101 highlight the therapeutic potential for a VISTA-directed immunotherapy unhindered by dose limiting toxicities and off-target effects. We believe the initial clinical data we presented from our Phase 1/2 clinical study further support these important preclinical findings. We are excited to see the impact SNS-101 can have in patients as we advance our ongoing clinical study."

The manuscript published in Nature Communications is entitled "VISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safety and pharmacokinetic profiles enhances PD-1 response," and can be found here: View Source

On April 4, 2024 Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL) reported a peer-reviewed publication in Leukemia & Lymphoma on data from an analysis of the Phase 2 study evaluating REZLIDHIA (olutasidenib), a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase-1 (mIDH1)1, in patients with mIDH1 acute myeloid leukemia (AML) who were relapsed/refractory (R/R) to prior venetoclax-based regimens (Press release, Rigel, APR 4, 2024, View Source [SID1234641788]).

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"Venetoclax in combination with a hypomethylating agent is currently standard treatment for patients with newly diagnosed AML who are unfit for intensive chemotherapy, including those with mIDH1. When this therapy fails, patients historically have had limited treatment options and poor prognoses," said Jorge E. Cortes, M.D., Director, Georgia Cancer Center, Cecil F. Whitaker Jr., GRA Eminent Scholar Chair in Cancer, and Phase 2 trial investigator. "The findings from these analyses suggest that REZLIDHIA may provide an effective treatment for patients with AML following failure of venetoclax combination therapy. REZLIDHIA induced durable remissions consistent with those observed in the pivotal trial and had a favorable tolerability profile in this challenging to treat patient population, representing a valuable treatment option."

"These data support REZLIDHIA’s efficacy and well-characterized safety profile in patients with mIDH1 R/R AML who had previously been treated with venetoclax combination regimens," said Raul Rodriguez, Rigel’s president and CEO. "These analyses are important because they provide valuable insights into the potential benefit of REZLIDHIA in different segments of the mIDH1 R/R AML patient population."

Key points from the paper are summarized below:

Olutasidenib alone or in combination with azacitidine demonstrated potential efficacy in patients with AML following failure of venetoclax combination therapy
Of the 18 patients with prior venetoclax treatment, 10 were relapsed, 6 were refractory, and 2 had complete remission with incomplete hematologic recovery (CRi) to a venetoclax combination
Of the 16 R/R patients, 7 (43.8%) achieved a composite complete remission (CRc), 4 (25%) achieved complete remission (CR), and 1 (6.3%) achieved CR with partial hematologic recovery (CRh). Both patients with CRi at study entry achieved CR
Median time to CRc was 1.9 months (range 1-2.8). As of the data cut-off (June 18, 2021), median duration of CRc was not reached (range, 1.2-NR, ongoing at 30.4+ months)
Red blood cell and platelet transfusion independence was achieved in 2/12 (17%) and 2/7 (29%) transfusion-dependent R/R patients at baseline, respectively
Safety was consistent with the overall profile of olutasidenib
The paper, titled "Olutasidenib in post-venetoclax patients with mutant isocitrate dehydrogenase 1 (mIDH1) acute myeloid leukemia (AML)," was published online in Leukemia & Lymphoma and can be accessed here.

About AML
Acute myeloid leukemia (AML) is a rapidly progressing cancer of the blood and bone marrow that affects myeloid cells, which normally develop into various types of mature blood cells. AML occurs primarily in adults and accounts for about 1 percent of all adult cancers. The American Cancer Society estimates that there will be about 20,800 new cases in the United States, most in adults, in 2024.2

Relapsed AML affects about half of all patients who, following treatment and remission, experience a return of leukemia cells in the bone marrow.3 Refractory AML, which affects between 10 and 40 percent of newly diagnosed patients, occurs when a patient fails to achieve remission even after intensive treatment.4 Quality of life declines for patients with each successive line of treatment for AML, and well-tolerated treatments in relapsed or refractory disease remain an unmet need.

About REZLIDHIA

INDICATION
REZLIDHIA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

Differentiation syndrome, which can be fatal, can occur with REZLIDHIA treatment. Symptoms may include dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, hypotension, fever, and weight gain. If differentiation syndrome is suspected, withhold REZLIDHIA and initiate treatment with corticosteroids and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS

Differentiation Syndrome
REZLIDHIA can cause differentiation syndrome. In the clinical trial of REZLIDHIA in patients with relapsed or refractory AML, differentiation syndrome occurred in 16% of patients, with grade 3 or 4 differentiation syndrome occurring in 8% of patients treated, and fatalities in 1% of patients. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with REZLIDHIA included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain. Of the 25 patients who experienced differentiation syndrome, 19 (76%) recovered after treatment or after dose interruption of REZLIDHIA. Differentiation syndrome occurred as early as 1 day and up to 18 months after REZLIDHIA initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, temporarily withhold REZLIDHIA and initiate systemic corticosteroids (e.g., dexamethasone 10 mg IV every 12 hours) for a minimum of 3 days and until resolution of signs and symptoms. If concomitant leukocytosis is observed, initiate treatment with hydroxyurea, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms. Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment. Institute supportive measures and hemodynamic monitoring until improvement; withhold dose of REZLIDHIA and consider dose reduction based on recurrence.

Hepatotoxicity
REZLIDHIA can cause hepatotoxicity, presenting as increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased blood alkaline phosphatase, and/or elevated bilirubin. Of 153 patients with relapsed or refractory AML who received REZLIDHIA, hepatotoxicity occurred in 23% of patients; 13% experienced grade 3 or 4 hepatotoxicity. One patient treated with REZLIDHIA in combination with azacitidine in the clinical trial, a combination for which REZLIDHIA is not indicated, died from complications of drug-induced liver injury. The median time to onset of hepatotoxicity in patients with relapsed or refractory AML treated with REZLIDHIA was 1.2 months (range: 1 day to 17.5 months) after REZLIDHIA initiation, and the median time to resolution was 12 days (range: 1 day to 17 months). The most common hepatotoxicities were elevations of ALT, AST, blood alkaline phosphatase, and blood bilirubin. Monitor patients frequently for clinical symptoms of hepatic dysfunction such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Obtain baseline liver function tests prior to initiation of REZLIDHIA, at least once weekly for the first two months, once every other week for the third month, once in the fourth month, and once every other month for the duration of therapy. If hepatic dysfunction occurs, withhold, reduce, or permanently discontinue REZLIDHIA based on recurrence/severity.

ADVERSE REACTIONS
The most common (≥20%) adverse reactions, including laboratory abnormalities, were aspartate aminotransferase increased, alanine aminotransferase increased, potassium decreased, sodium decreased, alkaline phosphatase increased, nausea, creatinine increased, fatigue/malaise, arthralgia, constipation, lymphocytes increased, bilirubin increased, leukocytosis, uric acid increased, dyspnea, pyrexia, rash, lipase increased, mucositis, diarrhea and transaminitis.

DRUG INTERACTIONS

Avoid concomitant use of REZLIDHIA with strong or moderate CYP3A inducers.
Avoid concomitant use of REZLIDHIA with sensitive CYP3A substrates unless otherwise instructed in the substrates prescribing information. If concomitant use is unavoidable, monitor patients for loss of therapeutic effect of these drugs.
LACTATION
Advise women not to breastfeed during treatment with REZLIDHIA and for 2 weeks after the last dose.

GERIATRIC USE
No overall differences in effectiveness were observed between patients 65 years and older and younger patients. Compared to patients younger than 65 years of age, an increase in incidence of hepatotoxicity and hypertension was observed in patients ≥65 years of age.

HEPATIC IMPAIRMENT
In patients with mild or moderate hepatic impairment, closely monitor for increased probability of differentiation syndrome.

Click here for Full Prescribing Information, including Boxed WARNING.

To report side effects of prescription drugs to the FDA, visit www.fda.gov/medwatch or call 1-800-FDA-1088 (800-332-1088).

REZLIDHIA is a registered trademark of Rigel Pharmaceuticals, Inc.