On June 6, 2022 GRAIL, LLC, a healthcare company whose mission is to detect cancer early when it can be cured, reported that the study design of the NHS-Galleri trial was presented at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Grail, JUN 6, 2022, View Source [SID1234615658]). The poster, titled "NHS-Galleri Trial Design: Equitable Study Recruitment Tactics for Targeted Population-Level Screening With a Multi-Cancer Early Detection (MCED) Test," was presented by Professor Charles Swanton, MD, PhD, a cancer researcher and oncologist at University College London and the Francis Crick Institute, chief clinician, Cancer Research UK, and co-chief investigator of the study (Abstract #TPS6606).

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The NHS-Galleri trial is a randomized and controlled clinical trial in the NHS’ clinical practice setting. It is the largest study of an MCED test, enrolling 140,000 healthy volunteers aged 50-77 in select regions throughout England who have not had a cancer diagnosis or undergone treatment for cancer in the last three years. Regions in the UK were selected to include areas of high cancer mortality, socioeconomic deprivation and ethnic diversity, using innovative methods to enroll a study population with a reasonable number of participants from all socioeconomic groups and major ethnic minority groups.

The study’s aim is to determine if the Galleri test, along with other standard cancer screenings, can find cancers at an early stage when they are less advanced, and patients have a higher chance of successful and potentially curative treatment. It will assess absolute numbers of stage 3 and 4 cancers diagnosed at 3.5 years following randomization.

"This study has the potential to be game changing for early cancer detection, as we evaluate an unprecedented number of healthy volunteers and work to ensure participants are representative of the entire population with cancer," said Dr. Swanton. "Unfortunately, many cancers are found too late, when they are more advanced and difficult to treat. We know early diagnosis saves lives, and we think this test could be a key to increasing cancer survival rates for more people."

The collaboration between GRAIL and the NHS supports the NHS Long Term Plan to transform cancer care with three in four cancers diagnosed at an early stage by 2028. More than 100,000 participants have been enrolled to date. Enrollment is expected to be completed in July 2022, and initial trial results are expected in 2024. If successful, the NHS plans to extend the rollout to an additional 1 million people in 2024 and 2025.

"We share a commitment with the NHS to have data that is representative of society at-large and all people with cancer and ensuring that access to cancer screening and earlier diagnosis is accessible and equitable," said Josh Ofman, MD, MSHS, president, GRAIL. "The current approach for screening and diagnosing cancer is not as effective as it could be and we are committed to changing the status quo. We are proud to be working with the NHS on this groundbreaking, large-scale, population screening program that has the potential to fundamentally transform early cancer detection."

In a clinical study, the Galleri test demonstrated the ability to detect signals across more than 50 types of cancer, as defined by the American Joint Committee on Cancer Staging Manual, over 47 of which lack recommended screening tests today in the UK. GRAIL’s Galleri test has a false positive rate under 1% and it can predict where cancer originated with 89% accuracy.

"We applaud the UK Government and the NHS for their leadership in setting the roadmap to achieve their goal of diagnosing three-quarter of all cancers at an early stage by 2028," said Sir Harpal Kumar, president of GRAIL Europe. "A reduction in late-stage cancer is thought to precede a reduction in deaths and is also associated with other beneficial patient outcomes, including the ability to receive effective therapy and improve quality of life."

About NHS-Galleri trial

For the prospective, partially blinded, randomized trial, all study participants will provide a blood sample during three annual visits to a mobile health clinic—at baseline, year 1 and year 2. After the first visit, participants are randomized 1:1 into either the intervention or control arm. Participants in the intervention arm will have their blood tested by the Galleri test. Blood samples from subjects in the control arm will not be tested immediately, but will be stored for potential future testing. If a cancer signal is detected for those in the intervention arm, research staff will explain the result and schedule an appointment for follow-up tests at an NHS hospital local to the participant. All participants in the study will be followed for cancer and other related outcomes via NHS databases and will be reminded to continue to have guideline-recommended cancer screenings.

The study is sponsored by GRAIL and is being run by Cancer Research UK and King’s College London Cancer Prevention Trials Unit (UK), in collaboration with eight cancer alliances in England.

On June 6, 2022 AnHeart Therapeutics ("AnHeart"), a clinical-stage global biopharmaceutical company committed to developing novel precision oncology therapeutics, and Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, autoimmune, metabolic, ophthalmology and other major diseases, reported that updated efficacy and safety data from the Phase 2 TRUST clinical trial of taletrectinib in patients with ROS1-positive non-small cell lung cancer (NSCLC), at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, AnHeart Therapeutics, JUN 6, 2022, View Source [SID1234615657]).

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The Efficacy and Safety of Taletrectinib in TKI-naïve or Crizotinib-pretreated ROS1-positive Non-Small Cell Lung Cancer (NSCLC) Patients

Poster Presentation, Abstract #: 8572

The ongoing TRUST study (NCT04395677) is a multicenter, open-label, single-arm, Phase 2 study of taletrectinib in Chinese ROS1-positive NSCLC patients who are ROS1 tyrosine kinase inhibitor (TKI)-naive or crizotinib-pretreated.

As of February 23, 2022, the Phase 2 TRUST study has enrolled 67 TKI-naive and 42 crizotinib-pretreated patients. The patients were treated with taletrectinib 600 mg once daily and evaluated by independent review committee (IRC) for key efficacy endpoints including objective response rate (ORR), duration of response (DOR), disease control rate (DCR), intracranial objective response rate (IC-ORR), intracranial disease control rate (IC-DCR), progression-free survival (PFS), overall survival (OS), and safety.

In ROS1 TKI-naïve patients, the cORR was 92.5% (62/67), including 2 confirmed complete response (cCR); and DCR was 95.5% (64/67).
In crizotinib-pretreated patients, the cORR was 50% (19/38), DCR was 78.9% (30/38).
Of the 5 crizotinib-pretreated patients who had ROS1 G2032R mutation, 4 achieved cPR, and 1 achieved SD.
Of the 12 patients with brain metastasis and measurable brain lesions at baseline, the IC-ORR and IC-DCR were 91.7% and 100%, respectively. The brain tumors disappeared completely in one patient who had only non-measurable brain lesions at baseline.
Taletrectinib was generally well tolerated. Most treatment emergent adverse events (TEAEs) were Grade 1 or 2. The most frequently reported treatment-related adverse events (TRAEs) for patients on taletrectinib were low-grade diarrhea and transient AST/ALT elevation without increase in bilirubin. Low incidence of neurological AEs was reported. The selective inhibition of ROS1 over TRKB by taletrectinib may help significantly reduce TRKB-related CNS adverse events. Some common adverse events that are frequently reported in other ROS1 inhibitors, such as vision disorders, edema, headache, dizziness, and musculoskeletal disorders were observed less frequently in taletrectinib.
"Taletrectinib is a potential best-in-class next-generation ROS1 inhibitor that is a much-needed new option to treat both ROS1-TKI-naïve and pre-treated NSCLC patients," said Dr. Caicun Zhou, primary investigator and chief oncologist at Shanghai Pulmonary Hospital. "The TRUST study showed high objective response rates in both the first-line and second-line settings in ROS1-positive NSCLC, with excellent potency against crizotinib-resistant mutations, including G2032R solvent front mutation. We’re excited to see that taletrectinib has also demonstrated intracranial antitumor activity in patients with brain metastases."

"Taletrectinib reported better brain penetration and intracranial activity in reference to other ROS1 inhibitors, with a favorable safety profile," said Dr. Bing Yan, Global Chief Medical Officer and Co-Founder of AnHeart. "We look forward to advancing taletrectinib, as we believe it is a potential best-in-class next-generation ROS1 inhibitor for both ROS1 TKI-naïve and ROS1 TKI-pretreated NSCLC patients, who are in need for new therapeutic options that have antitumor activity against resistant mutations and brain metastases."

"The updated ORR and DCR data of taletrectinib demonstrated its potential superior benefits in terms of both efficacy and safety for Chinese patients with ROS1-positive NSCLC," said Dr. Hui Zhou, Senior Vice President of Innovent. "We are encouraged by the results and will move towards further clinical development of taletrectinib to explore the potential of the next-generation ROS1 inhibitor and benefit more NSCLC patients in the future."

ROS1 oncogenic fusions are observed in ~1-2% NSCLC patients as well as in cholangiocarcinoma, glioblastoma, ovarian, gastric, and colorectal cancers. CNS metastasis occurs in 20-30% ROS1 TKI-naïve and in up to 50% of crizotinib-pretreated ROS1-positive NSCLC patients. Resistance to first-generation ROS1 inhibitors often occurs with secondary mutations such as ROS1 G2032R solvent front mutation, for which no FDA-approved therapy is available.

Taletrectinib is a next-generation, CNS-penetrant, selective ROS1 inhibitor. In March 2022, the NMPA grants Breakthrough Therapy Designation (BTD) to taletrectinib for both first-line TKI-naïve and second-line TKI-pretreated patients with ROS1-positive NSCLC.

A separate global Phase 2 trial TRUST-II (NCT04919811) is actively enrolling patients at clinical sites in North America, Europe and Asia. The design of the TRUST-II study is presented in the poster (#TPS8601) at ASCO (Free ASCO Whitepaper) 2022.

ABOUT TALETRECTINIB

Taletrectinib1 is a novel best-in-class next-generation ROS1 inhibitor designed to effectively target ROS1 fusions with potential to treat both TKI-naïve and pre-treated patients. ROS1 rearrangement is estimated to be an oncogenic driver in approximately 1 to 2 percent of patients with NSCLC. ROS1 fusions are also observed in several other cancers such as cholangiocarcinoma, glioblastoma, ovarian, gastric, and colorectal cancers. Taletrectinib has demonstrated excellent potency against crizotinib resistance, good brain penetration and intracranial antitumor activity, and favorable safety profiles in ROS1 fusion-positive NSCLC patients. In these patients, few neurological adverse events were observed, which likely benefits from the selective inhibition of ROS1 over TRKB by taletrectinib. More information about the ongoing China TRUST (Taletrectinib ROS1 LUng STudy) phase 2 trial and the global TRUST-II phase 2 trial may be found by searching clinical trial identifiers NCT04395677 and NCT04919811, respectively at View Source For questions about the ongoing trials, please contact [email protected].

On June 6, 2022 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, reported that results from the Phase II SUMMIT trial, assessing the efficacy of combined neratinib, fulvestrant, and trastuzumab in patients with hormone receptor positive, HER2-negative, HER2-mutant metastatic breast cancer, at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting held in person from June 3-7 in Chicago, IL, and online (Press release, Puma Biotechnology, JUN 6, 2022, View Source [SID1234615656]). The poster, entitled "Neratinib + fulvestrant + trastuzumab (N+F+T) for hormone receptor-positive (HR+), HER2-negative, HER2-mutant metastatic breast cancer (MBC): outcomes and biomarker analysis from the SUMMIT trial," was presented at the Breast Cancer — Metastatic Poster Session (poster #1028) by Komal L. Jhaveri, MD, FACP, Medical Oncologist at Memorial Sloan Kettering Cancer Center on June 6 at 9:00 a.m. ET.

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Earlier genomic analyses from a cohort treated with a combination of neratinib and fulvestrant suggest that resistance to neratinib may occur via mutant allele amplification or secondary HER2 mutations. The addition of trastuzumab to the combination of neratinib and fulvestrant in this trial demonstrated positive durable responses in patients with HR-positive, HER2-mutant MBC who had received prior CDK4/6 inhibitors (CDK4/6i).

The Phase II SUMMIT basket trial is an open-label, multicenter, multinational study that included a cohort evaluating the efficacy of the triplet combination of neratinib (N), plus fulvestrant (F), plus trastuzumab (T), in patients with HR-positive, HER2-negative, HER2-mutant metastatic breast cancer, as identified by local genomic sequencing, who had previously received CDK4/6 inhibitors. In order to confirm the contribution of neratinib to the combination, a small, randomized cohort comparing neratinib plus fulvestrant plus trastuzumab versus fulvestrant plus trastuzumab versus fulvestrant was also included. A range of HER2 allelic variants was represented in the cohort. Patients who received the triplet regimen were enrolled in the non-randomized cohort and received 240 mg of neratinib per day intramuscularly, 500 mg intravenous fulvestrant on days 1 and 15 of Cycle 1 and then every 4 weeks, 8mg/kg body weight trastuzumab initially and then 6mg/kg every 3 weeks. Patients in the randomized cohort received either a combination of neratinib, fulvestrant, and trastuzumab, or fulvestrant and trastuzumab, or fulvestrant alone in a 1:1:1 ratio. To counter the side effects of diarrhea, loperamide prophylaxis was mandatory for the first two treatment cycles. Patients who were randomized to the combination of fulvestrant and trastuzumab, or fulvestrant alone, could cross over to receive neratinib, fulvestrant, and trastuzumab at progression. Efficacy was assessed using objective response rate (ORR) and clinical benefit rate (CBR). Tumor tissue was retrospectively assessed by central next-generation sequencing (NGS).

The table below summarizes the efficacy of SUMMIT MBC patients who received neratinib plus fulvestrant plus trastuzumab, those who received fulvestrant plus trastuzumab, and those who received fulvestrant alone; and also those who received fulvestrant plus trastuzumab or fulvestrant and then crossed over to neratinib plus fulvestrant plus trastuzumab upon progression. Patients who received neratinib plus fulvestrant plus trastuzumab (non-randomized + randomized) had a 35.3% investigator-assessed objective response rate, 14.3-month duration of response, 41.7% clinical benefit rate, and 8.2-month median progression-free survival. Neratinib appears to be a critical component of the combination therapy, as demonstrated by lack of response in the small cohort of patients treated with fulvestrant or fulvestrant plus trastuzumab, and by response in a subset of those patients upon crossover to neratinib plus fulvestrant plus trastuzumab.

Table: Efficacy Findings from HR+ Metastatic Breast Cancer Patients

Data cut-off: 15 April 2022. Tumor response based on: investigator tumor assessments (RECIST v1.1)
CR, confirmed response; PR, partial response; CI, confidence interval; DOR, duration of response; NA, not applicable; NE, not estimable; PFS, progression-free survival
a Objective response defined as either a complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met;
b Kaplan-Meier analysis. For crossover patients, calculated from time of crossover to N+F+T.
c Clinical benefit is defined as confirmed CR or PR or stable disease (SD) for ≥24 weeks (within +/– 7-day visit window)
These results suggest that the combination of neratinib, fulvestrant, and trastuzumab together is promising for treating HR+ and HER2-mutated MBC with prior exposure to CDK4/6i across a range of HER2 mutations.

Dr. Jhaveri, an investigator of the trial, said, "Patients with hormone receptor-positive, HER2-negative, HER2-mutant metastatic breast cancer who had received prior treatment with CDK4/6 inhibitors demonstrated encouraging clinical activity with durable responses when treated with the triplet combination of neratinib with fulvestrant and trastuzumab. These responses were observed in patients whose tumors harbored a wide spectrum of HER2 mutations, including those with co-occurring HER3 mutations, regardless of ductal or lobular histology, and with a range of HER2 protein expression."

Alan H. Auerbach, Chief Executive Officer, and President of Puma Biotechnology added, "HER2 mutations can be readily and accurately identified and are clinically actionable for targeted therapy in metastatic breast cancers. We are very pleased with the updated activity seen with the combination of neratinib plus trastuzumab plus fulvestrant therapy in this heavily pretreated metastatic breast cancer patient population with HER2-mutated disease."

On June 6, 2022 Onco360, the nation’s leading independent Specialty Pharmacy, reported that it has been selected by Myovant Sciences to be a specialty pharmacy partner for ORGOVYX (relugolix), which is a gonadotropin-releasing hormone (GnRH) antagonist that is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with advanced prostate cancer (Press release, Onco360, JUN 6, 2022, View Source [SID1234615655]).

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"Onco360 is honored to become a specialty pharmacy provider for ORGOVYX patients," said Benito Fernandez, Chief Commercial Officer, Onco360. "We are committed to supporting the highly specialized needs of patients battling advanced prostate cancer across the United States."

According to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program, it is estimated that 268,490 new cases of prostate cancer will be diagnosed in 2022 with a corresponding 34,500 deaths as a result of the malignancy. Prostate cancer is the most commonly diagnosed cancer in male patients. The median age at the time of initial prostate cancer diagnosis is 67 years old with 92.5% of cases occurring in patients who are at least 55 years old. When considering all stages of disease, prostate cancer has a 96.8% five-year overall survival (OS).1

ORGOVYX is commercialized by Myovant Sciences, Inc. and Pfizer, Inc. Please see the full prescribing information for ORGOVYX at Orgovyx Prescribing Information.

On June 6, 2022 Cellworks Group, Inc., a world leader in Personalized Medicine in the key therapeutic areas of Oncology and Immunology, reported results from the myCare-024-04 study, which demonstrate that the Cellworks Singula Therapy Response Index (TRI) was strongly predictive of Overall Survival (OS) and Progression-Free Survival (PFS) for newly diagnosed Glioblastoma Multiforme (GBM) patients (Press release, Cellworks, JUN 6, 2022, View Source [SID1234615654]). In this study, Singula TRI provided patient-specific estimates of OS and PFS for 18 NCCN guideline GBM therapies and provided predictive value beyond physician-prescribed therapy, patient age, patient sex, and MGMT methylation status.

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The results from the myCare-024-04 clinical study were featured in a poster presentation with comments from Dr. Manmeet Ahluwalia, M.D., M.B.A., Chief of Medical Oncology, Chief Scientific Officer and Deputy Director at Miami Cancer Institute, part of Baptist Health South Florida, at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting June 3-7th during the Central Nervous Systems Tumors Session and available online as Abstract 2053.

"The molecular heterogeneity of GBM is a key driver for the inconsistent therapy response rates that we see in brain cancer patients and makes the disease difficult to treat," said Patrick Wen, MD, Director, Center for Neuro-oncology, Dana-Farber Cancer Institute; Professor, Neurology, Harvard Medical School; and Co-Principal Investigator for the myCare-024-04 clinical study. "But by using a patient’s NGS data and Cellworks Singula to biosimulate their individual therapy responses, we can potentially improve the ability to select the most effective therapy for each GBM patient and positively effect clinical outcomes for brain cancer patients."

"The significant differences in treatment response among GBM patients necessitates moving beyond population-based treatments to personalized multi-gene therapy predictions," said Dr. Manmeet Ahluwalia, M.D., M.B.A., Chief of Medical Oncology, Chief Scientific Officer and Deputy Director at Miami Cancer Institute, part of Baptist Health South Florida; and Co-Principal Investigator for the myCare-024-04 clinical study. "Using Cellworks Singula TRI, we can simulate the molecular effects of cell signaling, drugs and radiation on patient-specific in silico diseased cells prior to treatment and then identify the magnitude of disease control and survival for specific anti-tumor strategies. The findings from using this approach in the myCare-024-04 study suggest that biosimulating guideline GBM therapies for newly diagnosed GBM patients can positively effect clinical outcomes."

The Cellworks Biosimulation Platform simulates how a patient’s personalized genomic disease model will respond to therapies prior to treatment and identifies novel drug combinations for treatment-refractory patients. The platform is powered by the groundbreaking Cellworks Computational Omics Biology Model (CBM), a network of 7,000+ human genes, 30,000+ molecular species and 100+ signaling pathways. As part of the biosimulation process, personalized disease models are created for each patient using their cytogenetic and molecular data as input to the Cellworks CBM. The Cellworks platform analyzes the impact of specific therapies on the patient’s personalized disease model and generates a Singula biosimulation report with Therapy Response Index (TRI) scores from 0 to 100 that predict the efficacy of specific chemotherapies.

myCare-024-04 Clinical Study

Background

In this study, the Cellworks Singula Therapy Response Index (TRI) was used to prospectively predict the Overall Survival (OS) and Progression-Free Survival (PFS) in a retrospective cohort of 270 IDH wildtype GBM patients from the Cancer Genome Atlas (TCGA) with known clinical outcomes treated with physician prescribed therapies. The cohort included 162 males and 108 females with a median age of 57.5 years.

Methods

A mechanistic mulit-omcis biology model created for each patient using comprehensive genomic inputs allows biosimulation of downstream molecular effects of cell signaling, drugs and radiation on a patient’s personalized in silico disease model. Stratified random sampling was used to split the data into independent training (N=153) and validation (N=117) subjects. Multivariate Cox Proportional Hazard and Proportional Odds models were used to model OS and PFS as a function of the pre-defined Singula TRI and clinical thresholds. Cox Proportional Hazards (PH) regression and likelihood ratio (LR) tests were used on the independent validation subjects to assess the hypothesis that Singula is predictive of OS and PFS above and beyond standard clinical factors.

Results

Using Cellworks Personalized Therapy Biosimulation, Singula TRI was significantly predictive of OS and PFS in univariate analyses and remained significantly predictive in multivariate analyses, which included patient age, patient sex, MGMT methylation status and drug class.

Conclusions

Cellworks Singula TRI facilitates selection of optimal personalized therapies by providing patient-specific estimates of OS and PFS for 18 NCCN guideline GBM therapies. This information may be used to estimate increases in OS and PFS when comparing Singula TRI recommended therapies verses standard care. These positive results suggest the utility of biosimulation-informed therapy selection to improve survival of GEA patients.