publication date: May. 1, 2020

Clinical Roundup

Phase III trial evaluating Libtayo in NSCLC halted because of significant OS improvement

The primary endpoint of overall survival was met in a phase III trial comparing the PD-1 inhibitor Libtayo (cemiplimab) to platinum-doublet chemotherapy in patients with first-line locally advanced or metastatic non-small cell lung cancer who tested positive for PD-L1 in ≥50% of tumor cells.

Libtayo is jointly developed and commercialized by Regeneron and Sanofi under a global collaboration agreement.

Based on a recommendation by the independent data monitoring committee to stop the trial early, the trial will be modified to allow all patients to receive Libtayo for this investigational use, the companies said. The data will form the basis of regulatory submissions in the U.S. and European Union  in 2020.

“While demonstrating a survival benefit in first-line NSCLC has been challenging for immunotherapies, the one FDA-approved anti-PD-1 monotherapy has changed the therapeutic paradigm,” George D. Yancopoulos, co-founder, president and chief scientific officer of Regeneron, said in a statement.

A protocol-specified interim analysis conducted by the independent data monitoring committee demonstrated that patients treated with Libtayo monotherapy had a significant increase in OS. Libtayo decreased the risk of death by 32.4% (HR=0.676; CI:0.525-0.870, p=0.002), compared to platinum-doublet chemotherapy, despite a third of patients entering the trial within the past six months and all chemotherapy patients being able to crossover to Libtayo if their disease progressed.

“This is the largest clinical trial evaluating a PD-1 inhibitor as a first-line monotherapy in patients with advanced non-small cell lung cancer with high PD-L1 expression,” John Reed, global head of Research and Development at Sanofi, said in a statement.

Libtayo was invented using Regeneron’s proprietary VelocImmune technology that utilizes a proprietary genetically-engineered mouse platform endowed with a genetically-humanized immune system to produce optimized fully-human antibodies. VelocImmune technology has been used to create multiple antibodies including Dupixent (dupilumab), Praluent (alirocumab) and Kevzara (sarilumab). Regeneron previously used these technologies to develop a treatment for Ebola virus infection, which is under review by the FDA, and is used in efforts to create preventative and therapeutic medicines for COVID-19.


Lynparza demonstrates OS benefit in phase III prostate cancer trial

The phase III PROfound trial of Lynparza (olaparib) in men with metastatic castration-resistant prostate cancer who have a homologous recombination repair gene mutation and have progressed on prior treatment with new hormonal agent treatments (e.g. enzalutamide and abiraterone) has demonstrated improvement in overall survival.

AstraZeneca and Merck sponsor Lynparza.

Results from the trial showed a statistically significant and clinically meaningful improvement in the key secondary endpoint of overall survival with Lynparza versus enzalutamide or abiraterone in men with mCRPC selected for BRCA1/2 or ATM gene mutations, a subpopulation of HRR gene mutations, the companies said.

The phase III PROfound trial had met its primary endpoint in August 2019, showing significantly improved radiographic progression-free survival in men with mutations in BRCA1/2 or ATM genes, and had met a key secondary endpoint of rPFS in the overall HRRm population.


GARNET study demonstrates potential of dostarlimab to treat recurrent or advanced endometrial cancer

The GARNET trial demonstrated that dostarlimab, an investigational anti-programmed death-1 (PD-1) monoclonal antibody, provided clinically meaningful results in women with recurrent or advanced mismatch repair-deficient endometrial cancer who progressed on or after a platinum-based regimen.

GlaxoSmithKline plc. is an investigator on the trial.

This updated analysis included patients with dMMR endometrial cancer who had measurable disease at baseline and ≥6 months of follow-up by the data cutoff (n=71). Patients received 500 mg of dostarlimab once every three weeks for four doses, followed by 1,000 mg once every six weeks until disease progression. The primary endpoints were confirmed objective response rate and duration of response , as assessed against RECIST v 1.1 by blinded independent central review. GARNET is the largest dataset evaluating an anti-PD-1 in endometrial cancer.

Treatment with dostarlimab showed an ORR of 42% (95% CI; 31-55) and a disease control rate of 58% (95% CI; 45-69). Overall, 13% of patients had a complete response and 30% of patients had a partial response. At the time of data cutoff, with a median follow up of 11.2 months, the median DOR had not been reached (1.87+ to 19.61+ months).


MD Anderson, Ipsen advance therapy with potential benefit for patients with lung, ovarian cancer

Researchers at the MD Anderson Cancer Center’s Therapeutics Discovery division and Ipsen Biopharmaceuticals reported the preclinical discovery and early-stage clinical development of IPN60090, a small-molecule inhibitor of the metabolic enzyme glutaminase (GLS1).

IPN60090, now under investigation in a phase I trial, may benefit certain patients with lung and ovarian cancers.

MD Anderson’s GLS1 program was initiated and advanced by a team of scientists in the Institute for Applied Cancer Science and Translational Research to Advance Therapeutics and Innovation in Oncologyplatforms, both engines within Therapeutics Discovery. Development of the program continues in collaboration with Ipsen, which licensed the therapeutic in 2018.

Findings and information about the ongoing trial were presented April 27 at the 2020 American Association for Cancer Research virtual annual meeting I by Jeffrey Kovacs, institute group leader with TRACTION and co-leader of the GLS1 program.

IACS drug-discovery scientists identified IPN60090 as a potent and selective inhibitor of GLS1 suitable for clinical trials, and translational researchers in TRACTION demonstrated its activity against subsets of lung and ovarian cancer preclinical models.

Further analysis revealed biomarkers of response, which have been leveraged to identify patients most likely to benefit. In lung cancers, mutations in the KEAP1 and NFE2L2 genes, which regulate response to oxidative stress, sensitize cells to treatment with IPN60090. Similarly, low expression of the metabolic protein asparagine synthetase (ASNS) in ovarian cancers predicts response to IPN60090 in preclinical models.

IPN60090 is under investigation in a phase I dose-escalation and dose-expansion study for patients with advanced solid tumors that harbor KEAP1/NFE2L2 mutations or have low ASNS levels.


Study: Disruptions in health insurance coverage are common, and affect cancer care and survival

A new study finds disruptions in health insurance coverage are common in the United States and are associated with poorer cancer care and survival. The study was published in The Journal of the National Cancer institute.

For years, experts have known that lack of health insurance coverage is associated with poor access and receipt of cancer care and survival in the United States. Meanwhile, disruptions in coverage are common among low-income populations and little is known how these disruptions can affect cancer care, from prevention and screening to diagnosis, treatment, and survival.

Disruptions can be caused by gaps in coverage or transitions between types of coverage (e.g., public and private) or between specific health insurance plans.

Researchers, led by American Cancer Society’s Robin Yabroff, conducted a systematic review of studies of health insurance coverage disruptions and cancer care and outcomes published between 1980 and 2019. They identified 29 observational studies for analysis.

In those studies, from 4.3% to 32.8% of adults experienced coverage disruptions. Those with coverage disruptions were less likely to receive cancer prevention or screening, and if diagnosed with cancer, they were more likely to have advanced disease, were less likely to receive treatment, and have worse survival than their counterparts without coverage disruptions.

“Our findings were consistent across multiple cancer sites, with several studies finding a ‘dose-response’ relationship, meaning the longer the disruption, the worse the care,” lead author Yabroff said in a statement. “The consistency of these findings across the cancer control continuum in our review highlights how important it is to minimize breaks in health insurance coverage to address cancer disparities and promote health equity.”


AI may help brain cancer patients avoid biopsy

A study from UT Southwestern researchers shows that artificial intelligence can identify a specific genetic mutation in a glioma tumor simply by examining 3D images of the brain—with more than 97% accuracy.

Such technology could potentially eliminate the common practice of pretreatment surgeries in which glioma samples are taken and analyzed to choose an appropriate therapy.

“Knowing a particular mutation status in gliomas is important in determining prognosis and treatment strategies,” Joseph Maldjian, chief of neuroradiology at UT Southwestern’s O’Donnell Brain Institute, said in a statement. “The ability to determine this status using just conventional imaging and AI is a great leap forward.”

The study used a deep-learning network and standard MRI to detect the isocitrate dehydrogenase gene, which produces an enzyme that in mutated form may trigger tumor growth in the brain.

Doctors preparing to treat gliomas often have patients undergo surgery to obtain tumor tissue that is then analyzed to determine the IDH mutation status. The prognosis and treatment strategy will vary based on whether a patient has an IDH-mutated glioma.

However, because obtaining an adequate sample can sometimes be time-consuming and risky—particularly if tumors are difficult to access—researchers have been studying non-surgical strategies to identify IDH mutation status.

The study, published this spring in Neuro-Oncology, differentiates itself from previous research in three ways:

  • The method is highly accurate. Previous techniques have often failed to eclipse 90 percent accuracy.

  • Mutation status was determined by analyzing only a single series of MR images, as opposed to multiple image types.

  • A single algorithm was required to assess the IDH mutation status in the tumors. Other techniques have required either hand-drawn regions of interest or additional deep-learning models to first identify the boundaries of the tumor then detect potential mutations.

“The beauty of this new deep-learning model is its simplicity and high degree of accuracy,” Maldjian said. “We’ve removed additional pre-processing steps and created an ideal scenario for easily transitioning this into clinical care by using images that are routinely acquired.”

Maldjian’s team developed two deep-learning networks that analyzed imaging data from a publicly available database of more than 200 brain cancer patients from across the U.S.

One network used only one series from the MRI (T2-weighted images), while the other used multiple image types from the MRI. The two networks achieved nearly the same accuracy, suggesting that the process of detecting IDH mutations could be significantly streamlined by using only the T2-weighted images.

Maldjian’s team will next test his deep-learning model on larger datasets for additional validation before deciding whether to incorporate the technique into clinical care.

Meanwhile, researchers are hoping to develop medications to inhibit IDH through ongoing national clinical trials. If effective, these inhibitors could combine with AI-imaging techniques to overhaul how some brain cancers are assessed and treated.


Mouse model study shows promise in treatment of medulloblastoma and ependymoma

Researchers have demonstrated a novel approach in mouse models that delivers appropriately-targeted chimeric antigen receptor CAR T-cell therapy directly into the cerebrospinal fluid that surrounds the tumor in an effort to treat medulloblastoma and ependymoma.

Researchers at Baylor College of Medicine, Texas Children’s Hospital and the Hospital for Sick Children reported their findings in Nature Medicine. The findings support further clinical studies to evaluate this strategy to treat pediatric brain cancers. A first-in-child clinical trial is recruiting patients at Texas Children’s Hospital and Baylor College of Medicine to test the safety and anti-tumor efficacy of this approach (NCT02442297).

“Recurrences of medulloblastoma and ependymoma can be disseminated throughout the lining of the brain and spinal cord, which are bathed in cerebrospinal fluid. This location offers the opportunity to deliver therapies into the cerebrospinal fluid compartment and could provide a better chance for the therapy to reach and eliminate the tumor than administering it through the bloodstream,” co-corresponding author Nabil Ahmed, associate professor of pediatrics and immunology, section of hematology-oncology at Baylor and Texas Children’s Hospital, said in a statement.

In the mouse model studies, CAR T cells were administered into the cerebrospinal fluid around the tumor or into the bloodstream of mice harboring multiple patient-derived medulloblastoma and ependymoma tumors. The tumor size and animal survival were studied for about 200 days.

The results showed that administering tumor-specific CAR T cells into the cerebrospinal fluid was more effective than administering them via the blood. The researchers found that combining immunotherapy with azacytidine was significantly more effective than either treatment alone.

Copyright (c) 2020 The Cancer Letter Inc.