AJMC Staff

-related news reported across MJH Life Sciences™.

Blind Patient With Retinitis Pigmentosa Achieves Partial Vision via Gene Therapy

According to clinical trial findings published last week, optogenetic methods were shown for the first time to partially restore vision in a blind human patient.

, researchers delivered the optogenetic treatment in a patient with retinitis pigmentosa, an inherited photoreceptor disease, through the channelrhodopsin called ChrimsonR. Working to genetically alter cells so they can produce channelrhodopsins or light-sensitive proteins, the research team chose to base the analysis on the ChrimsonR protein that senses amber light, which was noted to be safer for retinal cells than blue light used for other optogenetic research.

After developing specialized goggles that utilize a camera to capture and project visual images onto the retina at amber light wavelengths, the patient was found to locate, touch, and count objects on a white table placed in front of him.

Although the patient was not able to perform the exercises without the aid of specialized goggles, researchers found in their last evaluation of electroencephalography readings that brain activity was indeed related to a visual object, indicating that the retina was no longer blind after treatment.

VISION-1 Phase 3 Study of Presbyopia Therapeutic Garners Positive Topline Results

, Eyenovia announced this week that the VISION-1 clinical study examining the safety and efficacy of its pilocarpine formulation, MicroLine, met its primary end point in providing temporary improvement of near vision in adults with presbyopia.

Administered via dispenser, participants were randomized to receiver either a therapeutic dose of MicroLine or placebo, with those undergoing MicroLine showing a 3-line or more improvement in distance corrected near visual acuity (DCNVA) vs the other group in low light conditions at 2 hours post treatment.

Eyenovia noted that the VISION-1 results will be presented at an upcoming ophthalmic-focused medical meeting, and the trial will be followed by a second phase 3 registration study called VISION-2. Both studies are required by the FDA for approval, with findings serving as the basis for a planned New Drug Application submission to the FDA.

Identifying Diabetic Candidates for Cornea Transplant Donations

With diabetic donors comprising 30% to 35% of the cornea donor pool, an article by 

 highlights that not all corneal tissue from diabetics may be suitable for corneal transplant surgery, known as ketoplasty.

As a way to delineate which patients with diabetes can successfully donate their corneas for ketoplasty and which should not, researchers from Case Western Reserve University, University Hospitals, and the Jaeb Center for Health Research plan to examine transplant success and the loss of endothelial cells after 

Descemet membrane endothelial keratoplasty

, the most common procedure that high-volume corneal-transplant surgeons are performing.

Backed by a 5-year, $6.4 million grant from the National Eye Institute of the National Institutes of Health, the research team will also determine the impact of donor and recipient diabetes on study outcomes. The researchers say that the study will involve 16 eye banks and 30 clinical sites nationwide.

Articles

Highlighting the latest ophthalmology-related news reported across MJH Life Sciences™.

Ophthalmology Overview: Gene Therapy Partially Restores Vision in Blind Patient, Presbyopia Therapy, and More

Contraception Advice Lacking for Women With RA

 (RA) affects women of childbearing age, but most don’t currently use contraception nor were they counseled to do so by their health care provider, according to a study reported on by 

The disease-modifying antirheumatic drugs (DMARDs) used in RA may have potential teratogenic effects on the fetus. In an observational study, researchers examined 2 years’ worth of medical records from a rheumatology clinic in Colorado, with the primary outcome looking at the prevalence and type of contraceptive use in patients aged between 18 and 44 years old.

Of the 150 women included in the study, contraception methods were observed in 42.7%, with the most common method being oral contraceptives, used by 48.4%; 15.6% used a levonorgestrel intrauterine device.

A total of 86 patients were not on any form of birth control, and just 22% of those patients had received any form of counseling or developed a pregnancy plan.

During the time period reviewed, 44% started a new DMARD, and most— 56.1%—were not on contraception at the time. Most of those women did not receive guidance about contraception from their physician.

Early Results for Osteoarthritis Gene Therapy

Investigators recently reported on the safety and potential efficacy of 

 for osteoarthritis. FX201, or humantakinogene hadenovec, is a helper-dependent adenovirus serotype 5 that expresses Interleukin (IL)-1 receptor (IL-1Ra) antagonist as an intra-articular gene therapy, 

At the recent American Society of Gene & Cell Therapy (ASGCT) Virtual Meeting, researchers discussed a phase 1 open-label, single ascending dose trial in order to assess the therapy’s safety, tolerability, biodistributions, and preliminary clinical activity in patients with moderate-to-severe osteoarthritis in the knee. The ongoing trial follows IND-enabling toxicology studies and clinical-scale cGMP production.

The findings come from 24-week data from the low-dose cohort (n = 5). Patient ages ranged from 30 to 80 years old, and all had Western Ontario and McMaster Universities Osteoarthritis Index pain scores ≥ 4.0 - ≤ 9.0.

Overall, the therapy was considered well-tolerated; 2 patients experienced self-limited grade 2 index pain, swelling, and effusion in the knee). The investigators indicated these events may have been possibly related to conservative treatment management.

Treatment options for gout are limited, but recent results showed that patients maintained a therapeutic response at 6 months when treated with a combination of methotrexate and pegylated uricase.

By comparison, the response rate was just 42% for patients receiving pegloticase alone, a medication that is highly effective in lowering serum uric acid levels, by converting serum uric acid levels to allantoin, 

The multicenter, open-label efficacy and safety study enrolled 14 males with a history of uncontrolled gout, defined as an sUA ≥ 6 mg/dL, with an inability to maintain < 6 mg/dL on other therapies, intolerance to urate-lowering therapies (ULT), or functionally limiting tophaceous deposits.

Participants received 15 mg/week oral methotrexate as well as 1 mg/day folic acid for 4 weeks leading up to and throughout the 52 weeks of treatment. They then initiated pegloticase treatment (8 mg intravenous) every 2 weeks in conjunction with follow-up appointments. Patients also adhered to a prophylaxis regimen of colchicine and/or nonsteroidal anti-inflammatory drugs (NSAIDs) and/or low-dose prednisone ≤ 10 mg/day. The primary outcome focused on how many patients had sUA levels of < 6 mg/dL for ≥ 80% of the time during month 6.

At the 6-month mark, 11 out of 14 participants met the primary outcome; all 14 patients tolerated methotrexate and no new safety concerns were noted.

Birth control guidance provided to women taking rheumatoid arthritis therapies is lacking, and other rheumatology news reported across MJH Life Sciences™.

Rheumatology Rundown: Birth Control Guidance, Gene Therapy, Gout Treatment

Novartis, Gates Foundation to Research Gene Therapy for Sickle Cell Disease

The Bill and Melinda Gates Foundation and Novartis are collaborating to discover and develop a one-step, one-time gene therapy treatment to cure sickle cell disease, STAT News 

. Although the cause of sickle cell disease is understood and the people it affects are known, a cure has been difficult to pin down. Through a 3-year partnership, the companies aim to create a treatment that is affordable and simple enough to treat individuals anywhere in the world, including sub-Saharan Africa, where disease prevalence is high. Current gene therapy approaches are complex and expensive, and they create treatments for patients one at a time. With an initial funding amount of $7.28 million, the companies ultimately hope to create an off-the-shelf product.

Global Rate of New COVID-19 Cases Declines

In the past week, the rate of new coronavirus disease 2019 (COVID-19) cases has declined by 16% around the world, according to the World Health Organization. This decline comes even as more virulent strains of COVID-19 have caused new outbreaks in some regions, 

 In addition to the decline in cases, over the past week there has been a 10% reduction in the number of deaths worldwide, with the greatest drop in cases seen in Europe and the Americas. In the United States alone, the number of new infections decreased by nearly 24% in the past week.

Deadly storms across the country hampered COVID-19 vaccination efforts on Tuesday, forcing appointment cancellations and delaying vaccine deliveries, according to the 

. The surge of bad weather comes as the federal government rolled out new vaccination sites targeting hard-hit communities and seeks to boost the amount of vaccine sent to states to 13.5 million doses per week. Currently, the United States administers an average of 1.7 million doses per day, but the bad weather halted vaccinations in Pennsylvania, Illinois, Tennessee, and Missouri and is expected to disrupt shipments from facilities in Tennessee and Kentucky.

Novartis is teaming up with the Gates Foundation to develop a gene therapy for sickle cell disease; the World Health Organization reports a drop in global cases of coronavirus disease 2019 (COVID-19); storms hinder vaccine rollout across the United States. 

What We’re Reading: Sickle Cell Gene Therapy Partnership; Global COVID-19 Cases on Decline; Storms Slow Vaccine Rollout

Researchers reported Friday that a preclinical study may have discovered a gene therapy vector candidate for blood disorders like sickle cell disease (SCD) and beta-thalassemia that could avoid genome toxicity.

Sickle cell disease and beta-thalassemia are genetic blood disorders caused by errors in the genes for hemoglobin; they are referred to as beta-globinopathies due to mutations in the beta-globin gene.

Current clinical trials involve the transfer of the beta-globin gene, which requires integration of 3 to 4 copies per genome in most target cells. But this high proviral load may increase genome toxicity, limit effectiveness, and require myeloablation, a procedure in which the bone marrow is suppressed via chemotherapy or radiation before gene therapy starts.

Scientists led by the Children's Hospital of Philadelphia (CHOP) developed a new vector using an engineered lentivirus.

Current lentiviral vectors all contain the human beta-globin gene along with its promoter, 3 so-called hypersensitive sites that are important for gene transcription, and a truncated version of intron 2, which does not code for proteins.

The CHOP researchers hypothesized that including the full intron, rather than a truncated one, in addition to other genomic elements that promote uniform expression of the beta-globin gene would enhance beta-globin and functional hemoglobin expression.

They created 5 novel lentiviral vectors by combining different additional genomic elements and generated 3 vectors similar to those that have already been used in clinical trials, which they used to compare to their novel vectors.

Through their work in the lab and in treating mice with beta-thalassemia, the researchers found that one of their vectors, ALS20, expressed significantly higher transgenic hemoglobin levels than other current vectors.

Compared with the 3 benchmark vectors, ALS20 produced 157%, 84%, and 40% more adult hemoglobin.

At a lower dose, the increased hemoglobin production from ALS20 could help patients become transfusion independent and reduce the need for myeloablation. In addition, ALS20 viral particles did not contain unwanted genomic RNA byproducts, and mice treated with ALS20 exhibited normal physiology without any proliferative disorders or cancerous formations compared with controls.

"These results have many potential benefits for the successful treatment of patients affected by beta-globinopathies like sickle cell disease and beta-thalassemia, including a better dose response, a minimized chance of clonal expansion and tumorigenesis, a reduced cost of therapy, and a potentially reduced need for chemotherapy or radiation before beginning gene therapy," Laura Breda, PhD, research assistant professor at CHOP and first author of the paper, 

Breda L, Ghiaccio V, Tanaka N, et al. Lentiviral vector ALS20 yields high hemoglobin levels with low genomic integrations for treatment of beta-globinopathies. 

Published online January 29, 2021. doi: 10.1016/j.ymthe.2020.12.036

An engineered lentivirus was created to avoid some of the drawbacks associated with current gene therapy vectors for sickle cell disease (SCD) and beta-thalassemia.




Preclinical Study of Gene Therapy Vector for SCD, Beta-Thalassemia Shows Promise

FDA Accepts BLA for Merck’s Pneumococcal Conjugate Vaccine

 that the FDA accepted for priority review a Biologics License Application (BLA) for V114, an investigational 15-valent pneumococcal conjugate vaccine for the prevention of invasive pneumococcal disease in adults 18 years and older. The BLA and priority review designation of Merck’s vaccine comes amid results presented in phase 2 and phase 3 clinical studies in several adult cohorts, including healthy adults and at-risk populations such as those with chronic medical conditions and HIV. The FDA set a target action date for July 18, 2021, with the European Medicines Agency also reviewing an application for V114 in adults.

Biotech Company Bluebird Will Split Into 2 Companies

, bluebird bio, a pioneer in gene therapy, will be split into 2 publicly traded drug companies, with one focused on the treatment of severe genetic diseases and the other on treating forms of cancer. The move comes as values of shares of bluebird had fallen by more than 46% in the past year among difficulties winning commercial approvals in the United States and manufacturing concerns. The announcement came on the first day of the virtual JP Morgan 39th Annual Healthcare Conference.

Yesterday, the World Health Organization (WHO) said that a new variant of the novel coronavirus was reported in Japan and found in 4 people arriving from Brazil, although details of whether the variant is more infectious, like that found in the 

 and South Africa, remains to be determined. As reported by 

, WHO Director-General Tedros Adhanom Ghebreyesus noted that as the virus continues to spread worldwide, the chance of new changes in the virus increases. Experts say they have not seen evidence that the new variants cause more severe disease or are resistant to vaccines.

FDA accepts for priority review a Biologics License Application for V114, Merck's investigational 15-valent pneumococcal conjugate vaccine; bluebird bio will be split into 2 publicly traded drug companies; a new variant of coronavirus is reported in Japan.

What We’re Reading: Priority Review for Merck Pneumococcal Vaccine; Bluebird Bio Splits Into 2 Companies; Novel Coronavirus Variant in Japan

When the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (axi-cel) works in large B-cell lymphoma (LBCL), the results can seem miraculous. But this expensive treatment does not work for about a quarter of patients who receive it, and researchers who presented results at the recent annual meeting of the American Society of Hematology (ASH) think they know why.

In CAR T-cell therapy, a patient’s T cells are removed and engineered in a manufacturing process to express a receptor that will target and kill cancer kills. These CAR T cells are then reinfused back into the patient, and it is typically clear within a month whether the treatment has worked.

Researchers led by Robbie G. Majzner, MD, of Stanford University School of Medicine wanted to find out what went wrong when CAR T-cell therapy did take hold. They analyzed genetic samples from 51 patients who received axi-cel and learned that 25% of the patients had tumors that lacked a functioning version of the protein CD58. In all but 1 of these patients, the treatment did not produce lasting effects.

The researchers then confirmed their findings in a mouse model that lacked CD58; the team tested 3 different CAR T therapies in the mice, but none worked.

Are patients whose tumors lack CD58 out of luck? Perhaps not. The research team determined that CD58 helped activate the biological mechanisms that allowed the CAR T-cell therapy to kill cancer. So, the researchers added a different protein, CD2, the T-cell ligand for CD58, to the job of the missing protein.

CD2, the researchers wrote in their abstract, 

plays both an adhesive role and a costimulatory role in T cells.” In a series of experiments, they noted that blocking CD2 greatly reduced cytokine production after CAR stimulation, but this can be a sign the treatment is not working.

Conversely, by modifying CAR T cells with the additional protein, the researchers were able to show in additional experiments with mice that the treatment can work without CD58. This approach could be tested in clinical trials within the next 2 years.

The results would be of interest to payers, who have tried to create CAR T payment structures that reimburse drug makers only when the treatment works. However, there are many significant administrative costs for the institutions that must be absorbed somewhere, and this has created access issues for patients without commercial coverage.

“Achieving an uptick of 20% to 25% in the complete response rate would really bring cures to a large number of additional patients,” Majzner said 

. “Ultimately, we could potentially screen patients for CD58 status and provide a more precision approach to this therapy.”

Majzner RG, Frank MJ, Mount C, et al. CD58 aberrations limit durable responses to CD19 CAR in large B cell lymphoma patients treated with axicabtagene ciloleucel but can be overcome through novel CAR engineering. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020. Abstract 558.

The findings help explain why costly CAR T-cell therapy does not work for some patients.

Creating Personalized Immunotherapy in Large B-Cell Lymphoma

The combination of 2 immunotherapies—chimeric antigen receptor (CAR) T-cell therapy and an oncolytic virus—were more potent against solid tumors than CAR T-cell therapy alone in mouse models of cancer, according to a study released this week.

Anti-CD19 CAR T-cell treatment acts on the B cell antigen CD19, but not all tumors have a naturally occurring antigen that is uniformly present on tumor cells but not normal tissues.

Researchers at the City of Hope genetically engineered an oncolytic virus (OV19t) to enter tumor cells and force their expression of CD19 protein on their cell surface. The killed tumor cells released additional copies of the virus, propagating CD19 expression to adjacent tumor cells. Then, CD19-directed CAR T cells could recognize and attack these solid tumors.

The study used triple-negative breast cancer lines, as well as pancreatic, prostate, ovarian, and head and neck cancer, and also brain tumor cells. The CD19-CAR T cells were combined with OV19t in vitro and in therapeutic studies in mice.

The scientists hope that human trials testing the sequence of the oncolytic virus and CAR T could start in 2022.

, Saul Priceman, PhD, the study's senior author and an assistant professor in City of Hope's Department of Hematology & Hematopoietic Cell Transplantation, said the technology had certain advantages. Solid tumors, he said, “are surrounded by a brick wall—a so-called immunosuppressive tumor microenvironment. When a CAR T cell attempts to enter the tumor, survive, and kill cancer cells, it can't effectively because of this barrier.”

Researchers said that mice already cured of their cancer with the oncolytic virus and CAR T-cell combination demonstrated prolonged protective antitumor immunity.

“The immune system built a memory response to the tumor,” said Anthony Park, PhD, a postdoctoral fellow. “Once it eradicated tumors, following the initial combination treatment, the mice were shielded against tumor recurrences.”

 which means they are not typically responsive to immunotherapies; introducing the virus reversed the tumor’s harsh microenvironment, making it more receptive to CAR T-cell therapy, he said.

Park AK, Fong Y, Kim SI, et al. Effective combination immunotherapy using oncolytic viruses to deliver CAR targets to solid tumors. 

. 2020;(12)559:eaaz1863. doi:10.1126/scitranslmed.aaz186

Combining chimeric antigen receptor (CAR) T-cell therapy and an oncolytic virus were more potent against solid tumors than CAR T-cell therapy alone in mouse models of cancer.

Scientists Hopeful About Early Study Combining Oncolytic Virus, CAR T

Selinexor Is Approved Under Accelerated Pathway to Treat DLBCL

The FDA granted accelerated approval to selinexor (Xpovio, Karyopharm Therapeutics) for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The oral treatment is to be used after at least 2 lines of systemic therapy.

The approval was based on response rate as determined in the SADAL trial, a multicenter, single-arm, open-label trial in patients with DLBCL who had received 2 to 5 systemic regimens.

“The accelerated approval of oral Xpovio in patients with relapsed or refractory DLBCL is a significant milestone for the patients and families who currently have limited treatment options available for their disease,” Sharon Shacham, PhD, MBA, founder, president, and chief scientific officer of Karyopharm Therapeutics Inc., said in a statement. “This approval marks the first for an oral agent for patients with previously treated DLBCL and the first approval of any single drug for this highly aggressive type of lymphoma.”

The phase 2b study evaluated 134 patients who were given 60 mg of selinexor orally twice weekly for a 4-week cycle. The study had an overall response rate (ORR) of 29%, including 18 (13%) complete responses and 21 (16%) partial responses. Of the 39 patients who achieved a partial or complete response, 38% had a response duration of at least 6 months and 15% had a response duration of at least 12 months. ORR and response duration were assessed by an independent review committee.

The most common adverse events (AEs) were fatigue (63%), nausea (57%), decreased appetite (37%), and diarrhea (37%). Most AEs were grade 1 and 2. The most common treatment-related AEs were cytopenias and gastrointestinal and constitutional symptoms.

“For the significant number of patients with relapsed or refractory DLBCL, there is an important need for new therapies for this particularly vulnerable patient population. Unfortunately, despite often multiple types of chemotherapy and targeted drug combination therapy, many patients have disease [that] continues to progress,” said John P. Leonard, MD, the Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medicine and an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center, and a paid consultant to Karyopharm.

Because the approval was based on response rate under the FDA’s accelerated approval program, continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Selinexor will become commercially available immediately, according to Karyopharm, which plans to submit a marketing authorization application to the European Medicines Agency in 2021 for the therapy to treat relapsed or refractory DLBCL.

Selinexor is already approved in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma in adults who had received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody.

Shacham noted that this “is now the second commercial oncology indication for Xpovio, highlighting its novel mechanism of action, ease of administration, and ability to produce rapid and durable responses in patients with heavily pretreated disease.” 

Karyopharm announces FDA approval of XPOVIO (selinexor) for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). News release. Karyopharm Therapeutics Inc. June 22, 2020. Accessed July 15, 2020. https://investors.karyopharm.com/news-releases/news-release-details/karyopharm-announces-fda-approval-xpovior-selinexor-treatment

FDA Approves CAR T-Cell Therapy for Adults With R/R Mantle Cell Lymphoma

On July 24, 2020, FDA approved the third chimeric antigen receptor (CAR) T-cell therapy, this time granting a green light for Kite Pharma’s brexucabtagene autoleucel, the first cell-based gene therapy to treat relapsed or refractory mantle cell lymphoma (MCL).

The therapy, to be sold as Tecartus, will be used to treat adult patients with MCL who have relapsed or not responded to other treatments. This new CAR T-cell therapy will be created the same way as those already approved: Brexucabtagene autoleucel will be manufactured by collecting a patient’s T cells and genetically modifying them to include a new gene that helps target and kill lymphoma cells. The engineered T cells are then infused back into the patient.

FDA officials said the approval was based on ZUMA-2, a multicenter trial of 60 adults with refractory or relapsed MCL who were followed for at least 6 months after their first objective disease response. The complete remission rate after treatment was 62%, and the objective response rate was 87%.

That trial’s lead investigator, Michael Wang, MD, professor in the Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Center, said that advances in MCL have nonetheless left treatment gaps for some patients after initial therapy.

“Many patients have high-risk disease and are more likely to keep progressing, even after subsequent treatments,” Wang said in a statement. “The availability of Tecartus as the first-ever cell therapy for patients with relapsed/refractory MCL provides an important option with a response rate of nearly 90% and early clinical evidence suggesting durable remissions in later lines of therapy.”

This is the second CAR T-cell therapy approval for Kite Pharma. The company previously received approval for axicabtagene ciloleucel (Yescarta). Both therapies are subject to a Risk Evaluation and Mitigation Strategy due to the possibility of cytokine release syndrome and neurologic toxicities.

MCL is a form of non-Hodgkin lymphoma occurring in cells from the “mantle” zone of the lymph node. It is an aggressive cancer that mostly affects men 60 years and over.

FDA gave brexucabtagene autoleucel priority review and breakthrough therapy designations, and the treatment was handled through the accelerated approval pathway. It also received orphan drug status, with granted financial incentives to encourage drug development. 

1. FDA approves first cell-based gene therapy for adult patients with relapsed or refractory MCL. News release. FDA; July 24, 2020. Accessed July 24, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-adult-patients-relapsed-or-refractory-mcl

2. U.S. FDA approves Kite Pharma’s Tecartus, the first and only CAR T treatment for relapsed or refractory mantle cell lymphoma. News release. Kite; July 24, 2020. July 24, 2020. https://www.kitepharma.com/news/press-releases/2020/7/us-fda-approves-kites-tecartus-the-first-and-only-car-t-treatment-for-relapsed-or-refractory-mantle-cell-lymphoma?utm_source=twitter&utm_medium=s

3. Kite’s Yescarta (axicabtagene ciloleucel) becomes first CAR T therapy approved by the FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. News release. Gilead; October 18, 2017. Accessed July 24, 2020. https://www.gilead.com/news-and-press/pressroom/press-releases/2017/10/kites-yescarta-axicabtagene-ciloleucel-becomes-first-car-t-therapy-approved-bythe-fda-for-the-treatment-of-adult-patients-with-relapsed-or-refrac

Evidence-Based Oncology regulatory updates for August 2020 feature coverage of Kite Pharma's new CAR T-cell therapy and selinexor in DLBCL.

FDA Actions Include Third CAR T-cell Therapy

Companion Diagnostics in NSCLC Offer Substantial Survival Benefit, but Some Patients Still Miss Out

Paitents with non-small cell lung cancer (NSCLC) who received a companion diagnostic as part of their initial treatment had a 3-fold greater survival benefit than those who were not tested—yet some patients still don’t get tested.

That is what authors found in a study published July 6, 2020, in 

The investigators, who reported the study was the largest real-world study of its kind, said it confirms the frustration that surrounds precision medicine in cancer care.

“Despite level 1 evidence supporting the benefits of biomarker-driven therapeutic approaches and consensus among national and international guidelines for the routine use of [companion diagnostic] testing in NSCLC, it is not clear whether this evidence has translated to practice in real-world settings,” the authors wrote.

The results are based on an analysis of information from the Flatiron Health database using patient records from 2011 to 2018. The authors are from divisions of Roche and from Peter MacCallum Cancer Centre in Australia. Roche funded the study; it acquired Flatiron for $1.9 billion in 2018.

What impacts who gets tested and who does not? Authors say the data show women are more likely to be tested than men, smokers are less likely to be tested than nonsmokers, and Asians as a group are likely to be tested.

The study found that as of May 31, 2018, only 14,732 patients with nonsquamous NSCLC received a companion diagnostic test out of 33,742 adult patients eligible for testing in the Flatiron Health database. However, the percentage who received testing increased significantly over time: Only 21.7% of eligible patients with nonsquamous NSCLC were tested from 2011 to 2013, and 62.2% of these patients were tested from 2014 to 2018.

Companion diagnostic (CDx) testing identifies patients most likely to benefit from biomarker-driven treatments. Much of the promise in lung cancer treatment comes from use of testing to match patients with targeted therapies, checkpoint inhibitors, or combinations. The 2020 American Society of Clinical Oncology Virtual Scientific Program featured the CITYSCAPE

Most of the study focused on results for 17,555 patients who met the study’s analysis criteria. These patients had nonsquamous advanced NSCLC and were classified into 1 of 2 groups: the CDx group (n = 14,732) were those who tested for 1 of 4 driver mutations (ALK, BRAF, EGFR, or ROS1 positive or negative) analysis criteria. These patients had nonsquamous advanced NSCLC and were classified into 1 of 2 groups: the CDx group (n = 14,732) were those who tested and/or PD-L1 expression according to the Flatiron data; the no-CDx group (n = 2823) were those who did not have reported evidence of testing, including no CDx test or testing status unknown.

The patients had a mean age at diagnosis of 67.2 years, and two-thirds were white (67.1%). Most had insurance (91.7%). Among those tested, the median time from diagnosis to the first test was 19.0 days, and the median time from advanced diagnosis to first-line treatment was 33 days.

Differences between those tested and those not tested included the following:

• More patients in the CDx group (49.4%) received more than 1 line of therapy than patients in the no-CDx group (24.9%).

• In the CDx group, 75.9% had received test results before or at the start of treatment.

• Regional differences were seen: Patients living in the Northeast or West were more likely to get CDx tests than patients in the Midwest, with point estimate 1.30 (95% CI, 1.13-1.50) and 1.34 (95% CI, 1.15-1.57), respectively.

• Smokers were less likely to be tested than nonsmokers, with a point estimate of 0.35 (95% CI, 0.29-0.41).

• Although not many Asian patients were in the study (n = 473), Asians were more likely to be tested than White patients, with a point estimate of 2.55 (95% CI, 1.56-4.18). 

Being tested meant living longer: Patients with CDx testing had a longer median survival than those without (95% CI) at 13.04 months (range, 12.62-13.40) vs 6.01 months (range, 5.72-6.24). Patients with testing also had decreased mortality risk (unadjusted HR, 0.54; 95% CI, 0.52-57).

When patients had CDx testing and biomarker-driven therapy as their first-line treatment, the results were even more remarkable compared with those who did not have testing: Median survival was 18.00 months (range, 16.66-19.22) vs 6.01 (range, 5.72-6.24). Patients who had their first CDx on or prior to first-line treatment also had a longer median overall survival than those not tested (12.78 vs 6.01 months; 95% CI).

“Since the prognosis for patients with advanced NSCLC is generally very poor, a dire need exists for earlier initiation of care through diagnostic testing and biomarker-driven treatment strategies. Based on this, it is evident that a standard ‘one size fits all’ approach in the treatment of cancer and many other disease areas does not always result in optimal patient outcomes,” the authors concluded.

“Precision medicine, in contrast, is an expanding treatment approach that can help match patients to the most effective treatments sooner based on an individual’s characteristics, including specific molecular targets likely to respond to biomarker-driven therapies.”

1. John A, Shan RA, Wong WB, Schneider CE, Alexander M. Value of precision medicine in advanced non-small cell lung cancer: real-world outcomes associated with the use of companion diagnostics. Oncologist. Published online July 6, 2020. doi:10.1634/theoncologist.2019-0864

2. Roche completes acquisition of Flatiron Health. News release. Roche. April 6, 2018. Accessed July 15, 2020. https://www.roche.com/media/releases/med-cor-2018-04-06.htm

3. Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as firstline (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol. 2020;38(suppl 15):9503. doi:10.1200/JCO.2020.38.15_suppl.9503

4. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB–IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. Presented at: 2020 ASCO Virtual Scientific Program; May 28, 2020. Accessed July 17, 2020. https://meetinglibrary.asco.org/record/191929/abstract

 Find Payer Coverage for Liquid Biopsies Improves, Gaps Remain

The role of circulating tumor DNA (ctDNA) in cancer care has advanced quickly over the past 5 years, allowing doctors to select targeted therapies or identify why treatments aren’t working. To some degree, payer coverage has followed, but it has lagged in important ways, according to research published in 

Journal of the National Comprehensive Cancer Network.

The National Comprehensive Cancer Network (NCCN) is a group of cancer centers that develops treatment guidelines considered to be the “gold standard” for payers.

Because coverage for ctDNA-based testing panels, also known as “liquid biopsies,” can dictate access, authors from the University of California San Francisco (UCSF) and City of Hope in Duarte, California, examined how coverage had changed over time as clinical adoption increased.

Using the Canary Insights database to analyze 40,000 medical policies from both commercial and public payers, the authors found that coverage increased 38% between January 1, 2015, and July 1, 2019.

Highlights of their findings include the following:

• None of the policies provided coverage in 2016, but 38% did by mid-2019.

• The scope of policies increased from a single cancer type in 2017 to 12 types of cancer and from a single gene to 73 genes.

• The review found a trend toward use of testing across all cancer types, which the authors described as “an important shift.”

• Forty-five payers had specific policies barring coverage.

“Genomic ctDNA or liquid biopsy tests hold great potential to improve patient outcomes, although, as with any emerging test, it can be challenging to develop the most appropriate coverage policies,” said lead investigator Michael P. Douglas, department of Clinical Pharmacy, UCSF Center for Translational and Policy Research on Personalized Medicine, said in a statement.

 “We think that the increased coverage, especially Medicare coverage of pan-cancer use, will expand the use of liquid biopsy in clinical practice in the future. The hope is that results in more targeted care with better treatment and diagnostic options, leading to long-term benefits.”

The investigators noted a difference between the highly specific nature of policies in private plans compared with draft and future-effective local coverage determinations with Medicare Administrative Contractors, which offer policies that will cover Medicare beneficiaries and testing across different cancer types (pan-cancer use). Among the private plans, 87% were for non–small cell lung cancer (NSCLC), 47% were for EGFR testing, and 79% were for specific brand-name tests.

The authors describe the “conundrum” in payer coverage given how these blood-based tests are used. The ctDNA test can be used at the time of diagnosis to find genomic alterations to direct targeted therapy and if the disease progresses to determine “the mechanism of therapeutic resistance.”

A blood-based assay is faster and easier than a tissue-based test, and sometimes tissue-based tests are unavailable, the authors wrote. They concluded, “Given that genomic medicine is rapidly changing, payers and policymakers (eg, guideline developers) will need to continue to evolve policies to keep pace with emerging science and standards in clinical care.”

“The NCCN Guidelines for Non–Small Cell Lung Cancer currently state that ctDNA testing can be considered for monitoring purposes when a patient with a confirmed lung cancer diagnosis is medically unfit for invasive tissue sampling,” said David S. Ettinger, MD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, who chairs the NCCN Guidelines for NSCLC panel. Ettinger was not involved with this study.

“Although coverage is expanding, it still takes too long to adapt policies, which often vary from state to state,” he said. “We recommend specific testing be conducted as part of a broad molecular profiling, at least for advanced or metastatic disease.”

Ettinger said a liquid biopsy can take less time than a diagnosis based on a tissue sample, and if positive, the liquid results are “unambiguous” and can direct clinical decision-making. If negative, there is a 30% chance the ctDNA results are not accurate, so a tissue sample should follow.

1. Douglas MP, Gray SW, Phillips KA. Private payer and Medicare coverage for circulating tumor DNA testing: a historical analysis of coverage policies from 2015 to 2019. J Natl Compr Canc Netw 2020;18(7):866-872. doi:10.6004/jnccn.2020.7542

2. JNCCN study explores if insurance is keeping pace with trends in targeted cancer therapy. News release. National Comprehensive Cancer Network. July 7, 2020. Accessed July 15, 2020. https://www.nccn.org/about/news/newsinfo.aspx?NewsID=2189

NCCN Patient Guidelines Highlight Adverse Effects of Immunotherapy, CAR T-Cell Therapy

Although immunotherapy has become an important treatment option for some cancers and is often well tolerated, it can have different adverse effects (AEs) than traditional approaches, such as chemotherapy. The National Comprehensive Cancer Network (NCCN) recently released a new set of guidelines to help patients and caregivers understand the unique and severe AEs of immune checkpoint inhibitors (ICIs), a common type of immunotherapy.

The patient guidelines provide information on the evidence-based, expertconsensus clinical practice guidelines used by health care providers—but in consumer-friendly language so patients and caregivers can better understand treatment options.

“Immune checkpoint inhibitors have revolutionized our approach to the treatment of cancer,” John A. Thompson, MD, professor of medicine at the University of Washington and chair of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities panel, said in a statement.

 “ICIs are now approved by the FDA for treating more than a dozen forms of cancer, and the list is growing every year. However, by virtue of stimulating the patient’s immune white blood cells, ICI therapy sometimes causes serious [adverse] effects that mimic autoimmune disease, including significant rash and/or inflammation of the thyroid, liver, lungs, nervous system, glandular system, heart, or other organs.”

The guideline explains that immune-related AEs can start during or after immunotherapy, but most can be managed if identified and treated early. NCCN also released patient guidelines on the AEs of chimeric antigen receptor (CAR) T-cell therapy. Olalekan Oluwole, MD, of Vanderbilt-Ingram Cancer Center and a member of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities panel, explained that traditional chemotherapy attacks all cells and can leave patients with long-term complications, such as other forms of cancer, but CAR T-cell therapy attack cancer cells in a different and more targeted way.

“The targeting is akin to a heat-seeking missile that won’t stop until it takes out any cell with the target, leading to potential long-term or permanent remission,” Oluwole said in a statement.2 “CAR T is given one time, unlike chemotherapy, which is given over multiple cycles and could go on for months or years. However, patients are often surprised to learn that the single CAR T infusion includes a 28-day monitoring period during which they need to stay in close proximity to their treatment center.”

Patients are monitored for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In CRS, immune cells affected by the treatment release cytokines into the blood, which creates an intense systemic inflammatory response. In ICANS, there are a range of neurological AEs. However, both CRS and ICANS can be reversed if treated promptly, which is why patients are monitored closely following treatment.

“CRS can set in rapidly, pushing the patient’s body to very high temperatures and taking quite a toll,” said Oluwole. “However, we researchers are learning more about how to collaborate to predict toxicities and sharing knowledge on recognizing and treating them more quickly. The new NCCN Guidelines for Patients are yet another example of how we’re sharing this important information.” 

1. NCCN. NCCN Guidelines for Patients. Immunotherapy side effects: immune checkpoint inhibitors. Accessed July 15, 2020. https://www.nccn.org/patients/guidelines/content/PDF/immunotherapy-se-ici-patient.pdf

2. How to recognize side-effects from immunotherapy? New NCCN Guidelines for Patients can help News release. National Comprehensive Cancer Network. June 29, 2020. Accessed July 17, 2020. https://www.nccn.org/about/news/newsinfo.aspx?NewsID=2179

OneOncology Appoints John Fox, MD, Medical Director of Managed Care

OneOncology, a national partnership of independent oncology practices, announced on July 20, 2020, the appointment of John Fox, MD, as medical director of managed care. In his role, Fox will work with OneOncology partner practices to develop, evolve, and maintain value-based contracts with commercial and public payers.

“As the transition from fee-for-service to value-based contracts continues, Dr Fox will play an integral role in supporting partner practices to develop and optimize value-based care to achieve Quadruple Aim goals,” said Jeff Patton, MD, OneOncology’s CEO.

OneOncology is a Strategic Alliance Partner of 

®. Fox is a member of the editorial board of 

As community oncology practices transition to value-based care delivery through the implementation of alternative payment models, OneOncology supports its partner practices’ capacity for change through public policy advocacy and thought leadership, commercial health plan contract negotiation, and physician engagement and education initiatives.

OneOncology partner practices have collectively managed about 4500 episodes of care in each performance period of the Center for Medicare and Medicaid Innovation’s Oncology Care Model (OCM). OneOncology partner practices also participate in several commercial health plan value-based payment arrangements. OneOncology provides a scalable platform for generating insights, sharing best practices, and benchmarking key performance metrics among several of the most progressive practices in value-based care. “I’m excited to join OneOncology and apply my experience to help ensure that partner practices continue to succeed transforming from volume to value,” said Fox. “OneOncology has been at the forefront of understanding the OCM and helping to shape Medicare’s next value-based oncology care model. Applying our OCM experience and aligning through all commercial value-based contracts will help drive success for patients, providers, employers, and payers.”

Fox was most recently vice president and associate chief medical officer for medical affairs at Priority Health. His initiatives included shared decision-making, advanced care planning, integrated specialty pharmacy program and value-based benefit designs, and payment reform strategies, including oncology medical home initiatives and bundled payments.

Evidence-Based Oncology managed care updates for August 2020 feature coverage of liquid biopsies, companion diagnostics, and CAR T-cell therapy.

Best Cancer Tests Don't Reach All Who Need Them

Patients who receive chimeric antigen receptor (CAR) T-cell therapy are benefiting from a key advance in cancer care, albeit one that also comes with the risk of cytokine release syndrome (CRS) and other unique side effects. A 

 from the National Comprehensive Cancer Network (NCCN) explains the possible side effects of CAR T, including neurological ones.

In CRS, T cells that have been activated release cytokines that activate other immune cells; this in turn releases more cytokines into the bloodstream. Consequently, the patient can experience high fever, severe flu-like symptoms, and other complications; CRS typically requires a stay in the intensive care unit.

“Patients are often surprised to learn that the single CAR T infusion includes a 28-day monitoring period during which they need to stay in close proximity to their treatment center,” said Olalekan Oluwole, MD, Vanderbilt-Ingram Cancer Center, and a member of the NCCN Guidelines Panel for Management of Immunotherapy-Related Toxicities.

Besides CRS, the medical team is also watching for immune effector cell-associated neurotoxicity syndrome (ICANS)—a range of neurological side effects. Those may include delirium, nerve dysfunction, aphasia, seizures, and brain swelling.

Both CRS and ICANS are generally reversible if treated promptly.

CAR T therapy starts at $373,000 for a 1-time treatment, but severe complications can easily 

push the total cost of care to $1 million

The patient guide explains 2 possible side effects, cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, that need to be caught quickly in order to be reversible.