Yes
You have come upon the fabled lands where myths
Go when they die.


— James Fenton
The Pitt-Rivers Museum (1983)

As a medical student, I was struck by the number of times our teachers regaled us with the “Gordian Knot” myth as a paradigm for how we should approach understanding complex patients and seemingly indecipherable clinical data sets. As legend has it, the Gordian Knot was so complex that it was impossible to perceive where one strand began and another ended; thus, it could never be unraveled. The task was considered so great that anyone who could untie the knot was prophesized to become the ruler of a vast portion of the world as it was then known. According to one version of the legend, Alexander the Great considered the knot, and in a stroke of genius pulled out his sword and sliced the knot in half. In doing so he fulfilled the oracle’s prophesy. The lesson of this story, as espoused by my teachers, was that a simple solution frequently existed for most complex healthcare conundrums.


We now find ourselves in the midst of a golden era of cancer care in which insights gleaned from genomic data and our ability to leverage a growing armamentarium of targeted anti-cancer treatments routinely produce superior survival outcomes with an improved quality of life for many patients. Yet, these advances have come with questions and challenges about how to pay for these treatments, how to deliver them equitably to patients in need, and how to ensure that our systems of care become more patient-centered. Clinical reimbursement systems now repeatedly lag advances in cancer diagnostic and treatment technologies. The cost of some treatments (such as CAR T-cell therapies) have challenged existing payment models from both public and private payers. At the same time, our care portfolio continues to outpace our systems for delivering this care in financially sustainable ways. Rather than empower a path toward sustainable solutions, the naïve believe that a simple approach is possible. This has paralyzed us from coming to terms with the necessary complexity of what it will take to deliver precision medicine solutions to cancer patients in the future. It is time for the mythic “Gordian Knot” approach to the development of more effective and efficient cancer care delivery systems to die.

™ we look at the emergence of additional innovative anti-cancer treatments, such as the second generation of the BTK inhibitors, DNA-based therapies for glioblastoma patients, and the clinical opportunities for the detection of NRG1 gene fusion in selected patients. Beyond exploring new diagnostic and therapeutic opportunities for cancer patients, we also review the exciting potential avenues for how healthcare payment and clinical reimbursement might evolve to support sustainable delivery of innovative treatments. Mark Trusheim, MSc, of MIT discusses a long-awaited plan to improve the ability of Medicaid programs to pay for gene-based therapeutics. Keely Macmillan, MSPH, from Archway Health discusses how downside risk related to precision oncology and high-cost therapeutics can be sustainably managed in the context of oncology advanced alternative payment models.


As the practice and systems-based delivery of cancer care evolves at a breakneck pace, simple solutions are more likely to harm, than help, essential stakeholders. Effective new delivery and payment systems can only emerge, however, if healthcare leaders fully embrace the inescapable necessary complexity of creating these systems. The writer HL Mencken cynically noted that, “For every complex problem there is an answer that is clear, simple and wrong.” There are many avenues in which the “Gordian Knot” approach leads to false choices and ill-conceived simple solutions. Pithy myths are a poor paradigm for navigating complex dilemmas. The path toward the broad realization of innovative, financially sustainable, equitably-delivered cancer care is likely to be an arduous, painful journey. It is time to embrace that complexity and let the comforting myths die.

Articles

FROM THE EDITORS

From the Editor-in-Chief, Evidence-Based Oncology, August 2020.

Where Myths Go to Die

Once known as a paradigm changing class of precision oncology, or targeted, drugs,

 Bruton tyrosine kinase (BTK) inhibitors are now well established as treatment for several hematological malignancies. They are named for Lt Col Ogden C. Bruton, MD, chief of pediatrics at Walter Reed Army Medical Center in the 1950s, who in 1951 discovered the first host immunodeficiency in humans, X-linked agammaglobulinemia

The BTK protein is essential to helping B cells develop and mature into functional and  specialized white blood cells; these are part of the adaptive immune response in producing antibodies, or immunoglobulins.

 But mutations in the BTK gene, more than 600 of which have been identified, can lead to a sizeable reduction in the number of circulating B cells, along with reduced ability to fight infection, absence of the BTK protein, production of abnormal BTK protein, or cancer cell growth.

Mutated immunoglobulins essentially malfunction in their roles as antigen receptors on the surfaces of B cells, especially in the cancer space, by not recognizing antigens as damaging or by not sending the correct signals to destroy the malignant cells.

This is where BTK inhibitors come in: They help to trigger cell death by blocking the B-cell receptor signaling that leukemias and lymphomas use to grow and survive.

 The first-generation BTK inhibitor ibrutinib (Imbruvica) came to market in 2013, when it was approved by the FDA to treat adult patients with mantle cell lymphoma. A targeted treatment, it stops cancer cells from surviving and multiplying by blocking abnormal protein signaling.

 Other indications, as monotherapy or in combination, have been approved for chronic lymphocytic leukemia, Waldenström macroglobulinemia, small lymphocytic lymphoma, relapsed/refractory marginal zone lymphoma, and chronic graft-versus-host disease.

 Ibrutinib is a once-daily oral agent and can be used in the frontline and relapsed settings.

Despite its many benefits and indications, however, ibrutinib as BTK inhibition is also associated with numerous adverse effects (AEs) on nonmalignant cells, which range from common to uncommon and from mild to severe, making ibrutinib’s toxicity profile notorious.

Among the most severe AEs are hemorrhage; high blood pressure; heart rhythm irregularities, including ventricular arrhythmias, atrial fibrillation, and atrial flutter; second primary cancers (eg, skin, other organs); and tumor lysis syndrome.

 Some of the most common AEs, occurring in more than 30% of patients, are hematological (eg, decreased platelets, neutrophils, and hemoglobin), musculoskeletal, and respiratory in nature. 

Additional possible AEs include diarrhea, constipation, vomiting, skin infections, dizziness, dehydration, petechiae, arthralgia, stomatitis, rash, and fatigue.

 Ibrutinib carries warnings for use among those with bleeding problems, liver problems, and for those who are planning surgery or recently had surgery; women who are pregnant or thinking of becoming pregnant; women who breastfeed or plan to do so; and men with female partners capable of pregnancy.

Second-generation BTK inhibitors seek to improve upon first-generation agents like ibrutinib by having less cardiotoxicity, fewer AEs that result in stopping treatment, and fewer off-target effects. For example, ibrutinib inhibits the activity of 3 major off-targets: epidermal growth factor, which can result in severe skin toxicities

; interleukin-2 inducible kinase, which impairs natural killer cells’ cytotoxic abilities

; and the Tec family of kinases, decreasing their ability to aid in phosphorylation.

In updated results of the ASPEN trial presented at this year’s virtual American Society of Clinical Oncology (ASCO) 2020 Annual Meeting, zanubrutinib (Brukinsa), the most recent second-generation BTK inhibitor to hit the US market, was shown to have a survival advantage over ibrutinib in patients with Waldenström macroglobulinemia who lacked the MYD88 mutation typically associated with successful treatment.

ASPEN first compared zanubrutinib with ibrutinib in patients with Waldenström macroglobulinemia who have the 

mutation, and zanubrutinib was shown in December 2019 to increase the incidence of complete response (CR) or very good partial response (VGPR) by close to 46% compared with ibrutinib—28.9% vs 19.8%, respectively—in patients with relapsed or refractory disease.

The updated results, from 5 additional months of data, widened this gap, showing a 30.4% CR plus VGPR rate for zanubrutinib compared with 18.2% for ibrutinib, as well as less occurrence of atrial fibrillation/flutter of any grade, bleeding of any grade, major hemorrhage, diarrhea, and hypertension. In addition, patients without the MYD88 mutation had an overall response rate of 80.8%, which included a 50.0% major response rate—which itself included a VGPR rate of 26.9%—and 12-month progression-free survival of 72.4%.

Lead investigator, Constantine Tam, MBBS, MD, a clinical hematologist and professor at the Peter MacCallum Cancer Centre in Victoria, Australia, noted of zanubrutinib, “Those patients who potentially have a history of hypertension or have a history of atrial fibrillation—or have an abnormal ECG or abnormal echocardiogram—maybe they’re the ones who would be better off on [zanubrutinib] compared with ibrutinib. We think it’s how clean the targeting is.”

Zanubrutinib is associated with less incidence of muscle spasm, peripheral edema, pneumonitis, and pneumonia. In essence, fewer overall AEs with second-generation BTK inhibitors means less of a need to reduce dosing and a greater likelihood of being able to stay on treatment longer. Tam noted that most AEs happen with zanubrutinib during the first year on treatment, before their incidence plateaus, whereas prolonged treatment with ibrutinib has a greater chance of inflicting cumulative damage to the vascular system.20 Compared with first-generation BTK inhibitors, the second-generation drugs are associated with fewer concerns about primary and acquired drug resistance. For example, ibrutinib use among patients with relapsed/refractory mantle cell lymphoma has been shown to both have no effect on the disease and have a negative impact on additional therapies.

These resistance mechanisms of action are 2-fold. They are molecular, in that they involve sustained distal B-cell receptor signaling through PIK3-AKT (protein kinase B) pathway activation, NFkB pathway activation, and cell cycle progression. They also are therapeutic, in that lines of therapy administered after BTK inhibitors do not produce prolonged responses or exceptional overall survival.

Some of the strongest gains in this newer generation of BTK inhibitors, however, can be seen in the cardiovascular space, when compared with the toxicities of the first-generation inhibitors

that often lead to treatment discontinuation, especially among older, sicker patients who have a history of cardiac disease. In fact, most BTK inhibitors are prescribed for older patients, because the class of drugs is used primarily to treat chronic lymphocytic leukemia, for which the average age of onset is older than 60 years.

“I think it’s that a lot of the toxicities are related to off-target effects, meaning the binding of the BTK inhibitor drug to receptors or molecules that are not the ones that that they’re supposed to be treating the cancer for,” said Michael Kolodziej, MD, FACP, vice president and chief innovation officer, ADVI Health, in an interview with 

“The big ones that were identified with the first-generation inhibitors were cardiovascular, or hypertension and atrial arrhythmias, atrial fibrillation. And they were not rare side effects.”

Kolodziej explained that the second-generation drugs have fewer off-target effects—less cardiovascular toxicity, atrial arrhythmias, and hypertension—because of their improved toxicity profile, “largely because the drugs are just better at being BTK inhibitors. It’s not any more complicated than that.”

The chief challenge of the first-generation BTK inhibitors is that the AEs cause clinicians and patients to stop treatment with them, Kolodziej noted. The cancer does not become resistant, but the toxicities become unbearable and the patients become intolerant, he emphasized.

“The thinking is that the reduced cardiovascular side effects, the reduced bleeding, are going to allow a better persistence on the second-generation drugs,” he explained.

Indeed, in a pooled analysis of clinical trials of the second-generation BTK inhibitor acalabrutinib (Calquence), also presented in May at ASCO, lead author Richard R. Furman, MD, of Weill Cornell Medicine in New York, found that at a median follow-up of 26.4 months, 65% of patients were still on treatment. Of the 34% of patients who stopped acalabrutinib, half (17%) did so because their disease progressed; only 9% stopped due to treatment-related AEs.

Tolerability, especially as patients define it, is increasingly important to payers, starting with Medicare. The Center for Medicare and Medicaid Innovation has announced that it will incorporate patient-reported outcomes (PROs) into the Oncology Care First model, the proposed successor to the Oncology Care Model.

 Advocates for including PROs in payment models are encouraging drug developers to broaden definitions of tolerability, to include quality-of-life data in trial designs.

It’s a straightforward idea: When patients can tolerate treatment, it improves their chances of survival. “This is important,” Tam said during ASCO. “The longer you take the drug, the better your responses become.”

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2. Wyckoff AS. Dr. Bruton’s discovery set the stage for modern clinical immunology. American Academy of Pediatrics News. May 31, 2018. Accessed July 18, 2020. https://www.aappublications.org/news/2018/05/31/dyk053118

3. Buckley RH. [Commentary:] agammaglobulinemia, by Col. Ogden C. Bruton, MC, USA, Pediatrics, 1952;9:722-728. Pediatrics. 1998;102(suppl 1):213-215. https://pediatrics.aappublications.org/content/102/Supplement_1/213

4. Deane P. B cells: the antibody factories of the immune system. Life Extension Advocacy Foundation. August 22, 2017. Accessed July 18, 2020. https://www.lifespan.io/news/b-cells/

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6. Bruton tyrosine kinase inhibitor. Science Direct. Accessed July 18, 2020. https://www.sciencedirect.com/topics/medicine-and-dentistry/bruton-tyrosine-kinase-inhibitor

7. BTK inhibitors. Drugs.com. Updated January 7, 2020. Accessed July 18, 2020. https://www.drugs.com/drug-class/btk-inhibitors.html

8. Ibrutinib. MedlinePlus. Updated May 15, 2019. Accessed July 19, 2020. https://medlineplus.gov/druginfo/meds/a614007.html

9. Imbruvica approval history. Drugs.com. Updated 2020. Accessed July 19, 2020. https://www.drugs.com/history/imbruvica.html

10. Berger JA. The evolving role of BTK inhibitors in treating chronic lymphocytic leukemia — BTK inhibition: disease state effectiveness. Targeted Oncology. April 16, 2020. Accessed July 19, 2020. https://www.targetedonc.com/view/evolving-btk-cll?seriesVid=2

11. How does Imbruvica work? Imbruvica (ibrutinib). April 20, 2020. Accessed July 19, 2020. https://imbruvica.com/cll/how-does-imbruvica-work

12. Imbruvica. Chemocare. Accessed July 19, 2020. chemocare.com/chemotherapy/drug-info/imbruvica.aspx

13. Ghasoub R, Albattah A, Elazzazy S, et al. Ibrutinib-associated sever[e] skin toxicity: a case of multiple inflamed skin lesions and cellulitis in a 68-year-old male patient with relapsed chronic lymphocytic leukemia– case report and literature review. J Oncol Pharm Pract. 2020;26(2):487-491. doi:10.1177/1078155219856422

14. Bennett C. Ibrutinib may impair natural killer cell cytotoxic activity, study suggests. Cancer Therapy Advisor. June 19, 2019. Accessed July 19, 2020. https://www.cancertherapyadvisor.com/home/cancer-topics/lymphoma/ibrutinib-for-mantle-lymphoma-mcl-may-impair-naturalcyto-toxic-activity/

15. Patel V, Balakrishnan K, Bibikova E, et al. Comparison of acalabrutinib, a selective Bruton tyrosine kinase inhibitor, with ibrutinib in chronic lymphocytic leukemia cells. Clin Cancer Res. 2017;23(14):3734-3743. doi:10.1158/1078-0432.CCR-16-1446

16. Garcia-Sanz R, Dimopoulos MA, Lee H-P, et al. Updated results of the ASPEN trial from a cohort of patients with MYD88 wild-type (MYD88WT) Waldenström macroglobulinemia (WM). J Clin Oncol. 2020;38(15 suppl; abstr e20056). doi:10.1200/JCO.2020.38.15_suppl.e20056

17. Tam CSL, Opat S, D’Sa S, et al. ASPEN: results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM). J Clin Oncol. 2020;38(15 suppl; abstr 8007). doi:10.1200/JCO.2020.38.15_suppl.8007

18. BeiGene presents updated head to head results from phase 3 trial of zanubrutinib vs. ibrutinib in patients with Waldenström’s macroglobulinemia at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. News release. BeiGene; May 29, 2020. Accessed August 3, 2020. https://www.globenewswire.com/news-release/2020/05/29/2040883/0/en/BeiGene-Presents-Updated-Head-to-Head-Results-from-Phase-3-Trial-of-Zanubrutinibvs-Ibrutinib-in-Patients-with-Waldenström-s-acroglobulinemiaat-the-2020-American-Society-of-Clini.html

19. Caffrey M. Zanubrutinib pulls away from ibrutinib in update, shows durable responses in Waldenstrom patients lacking key mutation. The American Journal of Managed Care®. May 30, 2020. Accessed July 21, 2020. https://www.ajmc.com/conferences/asco-2020/zanubrutinib-pulls-away-from-ibrutinib-in-update-shows-durable-responses-in-waldenstrom-patients-lacking-key-mutation

20. Dr Constantine Tam discusses the benefits of zanubrutinib on cardiac effects. The American Journal of Managed Care®. May 31, 2020. Accessed July 22, 2020. https://www.ajmc.com/conferences/asco-2020/dr-constantine-tam-discusses-the-benefits-of-zanubrutinib-on-cardiac-effects

21. Hershkovitz-Rokah O, Pulver D, Lenz G, Shpilberg O. Ibrutinib resistance in mantle cell lymphoma: clinical, molecular and treatment aspects. Br J Haematol. 2018;181(3):306-319. doi:10.1111/bjh.15108

22. Chronic lymphocytic leukemia. CancerWall. Accessed July 24, 2020. https://cancerwall.com/chronic-lymphocytic-leukemia-lifeexpectancy-symptoms/

23. Furman RR, Byrd JC, Own RG, et al. Safety of acalabrutinib (acala) monotherapy in hematologic malignancies: pooled analysis from clinical trials. J Clin Oncol. 2020;38(suppl 15; abstr 8064). doi:10.1200/JCO.2020.38.15_suppl.8064

24. Bekele B, Macher D, Ferguson S, et al. Emerging trends in oncology management. Avalere Health. June 2, 2020. Accessed July 31, 2020. https://avalere.com/insights/emerging-trends-in-oncology-management

25. Basch E, Campbell A, Hudgens S, et al. A Friends of Cancer research white paper: broadening the definition of tolerability in cancer clinical trials to better measure the patient experience. Friends of Cancer Research. October 24, 2018. Accessed July 31, 2020. https://www.focr.org/sites/default/files/Comparative%20Tolerability%20Whitepaper_FINAL.pdf

COVER FEATURE

Fewer off-target effects mean second-generation BTK inhibitors offer less cardiotoxicity and allow patients to stay on them longer, increasing their efficacy.

Second-Generation BTK Inhibitors Hit the Treatment Bullseye With Fewer Off-Target Effects

A recent collaboration between a Netherlands-based biotech and a well-known US diagnostics company highlights the journey of cancer care today: The bispecific antibody zenocutuzumab, previously studied more broadly in solid tumors, is now being focused in the specific patients in whom it seems to work wonders. These patients have neuregulin 1 (NRG1) fusions, a rare but powerful oncogene driver that makes cancer particularly aggressively and deadly when it is present.

Gene fusions occur when 2 previously independent genes connect, producing increased amounts of abnormal protein that trigger and fuel tumor growth. There are many types of NRG1 fusions, involving different genes, and they are a culprit in many cancers with poor survival rates, such as lung cancers among patients who never smoked and pancreatic cancer.

Zenocutuzumab targets both HER2 and HER3 and blocks the interaction of the NRG1 fusion protein with its receptor HER3; it has shown success in treating cancers fueled by NRG1 gene fusions.

 In fact, Merus, the maker of zenocutuzumab, was studying the drug’s effectiveness in breast cancer when it shifted gears to focus on patients with this rare cancer driver.

That’s where Merus’ collaborator, Caris Life Sciences, comes in: Although the strategy of matching the therapy with patients whose cancer is driven by NRG1 fusions appears to be a winner, the companies say these fusions are rare, occurring in only 0.3% to 3.0% of non–small cell lung cancer (NSCLC), 0.5% to 1.5% of pancreatic ductal cancer, and less than 1.0 % of other tumor types, based on available literature.

 Thus, it takes effort to find patients eligible for a trial.

The agreement will tap Caris’ next-generation sequencing technology to identify patients eligible for Merus’ phase 1/2 eNRGy trial and its Early Access Program.

David Spetzler, PhD, MBA, MS, president and chief scientific officer of Caris Life Sciences, said in an interview with 

™ that when a patient receives molecular profiling, “We perform whole exome sequencing and whole transcriptome sequencing. We’re assessing every single gene in their DNA and every single gene in their RNA.” He explained that for NRG1 fusions, it is best to look at the RNA, so this is a standard part of testing.

“We’re able to identify those patients who have NRG1 fusions and assess the expression level of them as well,” he said. “So, not only can we see that the fusion event has occurred, but we can also get a sense of the magnitude of how big it is within that particular tumor type.”

The focus will be on pancreatic cancer, for which Merus received an orphan drug designation from the FDA on July 29, 2020.

 Caris will perform whole exome sequencing of DNA and whole transcriptome sequencing of RNA for certain cancer patients, and make those who potentially meet the criteria aware of the trial.

FDA’s action followed results from a proof-of-concept study presented in October 2019 at the American Association of Cancer Research/National Cancer Institute/European Platform of Cancer Research International Conference on Molecular Targets and Cancer Therapeutics. At that meeting, investigators presented results from 3 patients with NRG1 gene fusions: 2 with pancreatic cancer and 1 with NSCLC.

 The patients were not part of a clinical trial, but rather an expanded access program at Memorial Sloan Kettering.

The patients with pancreatic cancer were a 52-year-old male who achieved a partial response and a 34-year-old male achieved who achieved stable disease; both were treated for at least 7 months. A 54-year-old male treated for NSCLC achieved partial response after being treated for at least 4.5 months. Among the 117 patients treated in the entire study, most adverse events (AEs) were grade 1 or 2, less than 5% had a grade 3 AE, and none had a grade 4 event.

“Receiving orphan drug designation for zenocutuzumab is another important milestone for our lead program, and it validates the significant unmet need in patients with pancreatic cancer,” Bill Lundberg, MD, president, CEO, and principal financial officer of Merus, said in a statement. “We are pleased with the progress we are making in our ongoing global clinical trial and believe that zenocutuzumab has the potential to play a significant role in shifting the treatment paradigm for NRG1 fusion cancers from conventional chemotherapy to a personalized medicine approach.”

This shift in gears highlights the evolution of cancer treatment: The focus increasingly is not solely on tumor type but also on the biomarkers that the tumors or blood cancers present, and then on finding therapies that will target the genetic markers driving the cancer. In a review article on developing precision and personalized medicine strategies, authors from Rutgers University wrote in 2018 that this may make cancer treatment more complex, but it has many advantages, from sparing patients the AEs of medicines that won’t work to lowering costs.

Using testing to define the clinical trial population is hugely beneficial, the Rutgers team wrote. “By focusing on smaller populations, clinical trial size will shrink, substantially reducing the costs. In addition, the population admitted to the trial is more likely to respond to the therapy, reducing the risk associated with failed clinical trials,” the authors wrote in 

To that end, can the Caris technology identify patients who might be good candidates for 1 treatable target of a bispecific antibody, but not the other?

“There’s a lot behind that question,” Spetzler said, “but it’s a very complex answer. Whether a patient would be eligible for the drug is really up to the pharma company in terms of defining their inclusion and exclusion criteria.”

Generally, Spetzler said, testing technology is also moving toward “a much more rigorous approach” that defines the best biological pathway, not just the genes involved.

“There’s growing evidence that we should be moving away from gene-specific associations more toward pathway-associated associations, and so the more complex signatures really can start to untangle some of the inherent complexity of these molecular systems,” he said. “I actually believe that is the future of molecular diagnostics: We’re going to move away from these univariate assessments of disease toward very complex signatures.

“Nobody’s really doing it yet, but it’s coming for sure.” 

Mary Caffrey is the associate editorial director for Managed Markets, MJH Life Sciences.

1. Merus and Caris Life Sciences announce collaboration to detect NRG1 fusions in cancer patients. News release. Merus; July 13, 2020. Accessed July 14, 2020.  https://www.globenewswire.com/newsrelease/2020/07/13/2061475/0/en/Merus-and-Caris-Life-Sciences-Announce-Collaboration-to-Detect-NRG1-Fusions-in-Cancer-Patients.html

2. Mishra R, Patel H, Alanazi S, et al. HER3 signaling and targeted therapy in cancer. Oncol Rev. 2018;12(1):355. doi:10.4081/oncol.2018.355

3. Merus announces FDA orphan drug designation of zenocutuzumab for the treatment of pancreatic cancer. News release. Merus; July 27, 2020. Accessed July 29, 2020. https://www.globenewswire.com/

news-release/2020/07/27/2067850/0/en/Merus-announces-FDA-Orphan-Drug-Designation-of-Zenocutuzumab-for-the-Treatment-of-Pancreatic-Cancer.html

4. Ternyila D. FDA grants orphan drug designation to zenocutuzumab as treatment of pancreatic cancer. Targeted Oncology. Published July 29, 2020. Accessed July 29, 2020. https://www.targetedonc.com/view/fda-grants-orphan-drug-designation-to-zenocutuzumab-as-treatment-of-pancreatic-cancer

5. Plieth J. Triple meeting—targeted focus validates Merus’ change of tack. Evaluate Vantage. Published October 27, 2019. Accessed July 29, 2020. https://www.evaluate.com/vantage/articles/events/conferences/triple-meeting-targeted-focus-validates-meruss-change-tack

6. Krzyszczyk P, Acevedo A, Davidoff EJ, et al. The growing role of precision and personalized medicine for cancer treatment. Technology (Singap World Sci). 2018;6(3-4):79-100. doi:10.1142/S2339547818300020

An agreement will tap Caris Life Sciences' next-generation sequencing technology to identify patients for Merus’ phase 1/2 eNRGy trial.

Partnership to Find Patients With NRG1 Fusions for Zenocutuzumab Trial in Pancreatic Cancer

By grade school, most of us have a basic understanding of DNA, or deoxyribonucleic acid, the essential building block of human life. It’s what makes our eyes blue or our hair straight. DNA medicines, however, are less well known and historically have been unsuccessful in delivering what 25 years ago was touted as a revolution in therapeutics.

 Contrary to popular opinion, DNA medicines are not synonymous with “gene therapy,” but they have been challenged by the same biases and presumptions, and because of that, DNA medicines have failed to gain therapeutic ground in the treatment of human disease. Until now.

A recent resurgence of DNA medicines is due in large part to improvements in the technology that has enabled their reintroduction into the clinic. Over the past several years, Inovio, a small biotechnology company outside of Philadelphia, has begun to master the utility of DNA  medicines and to optimize their delivery for clinical use in treating and preventing human disease. Inovio is currently investigating its DNA medicines using a proprietary platform that couples optimization of DNA plasmids with effi cacy-enabling delivery through the use of a smart device known as Cellectra (

) to treat and protect people from precancer, cancer, and infectious diseases. This device uses a short electrical pulse to open pores in the cell, allowing plasmids to enter. This ensures efficient delivery of the DNA medicine, overcoming limitations of earlier approaches.

Most recently, the company has received signifi cant media coverage for INO-4800, a DNA vaccine designed in 3 hours and brought from the bench to the clinic in 83 days to support the fight against coronavirus disease 2019.

 But the company’s history dates back several decades to the creation of its first products, followed by clinical investigation into the treatment of human papillomavirus–related diseases, such as cervical intraepithelial neoplasia (CIN). Its most advanced DNA medicine candidate, VGX-3100, is currently in a phase 3 trial for the treatment of high-grade CIN.

The proprietary technology uses a computer algorithm to build DNA medicines that can target almost any antigen that can be presented to the human immune system through the major histocompatibility class I system. DNA medicines are built in the form of circular strands of synthetic DNA called plasmids, which can neither propagate nor integrate into the human genome.

These plasmids have several specific and unique characteristics:

• First, they are designed to produce an optimal immune response when translated by the cell in which they are taken up.

• Second, they are able to be designed to any antigen that the human immune system can recognize.

• Third, they are translated as full-length proteins, which allow the cell to process and present the encoded antigen as intended by the native immune system.

• Finally, they are able to be kept, stored, transported, and dosed under a range of conditions and temperatures that support an extended shelf-life and optimal supply chain.

Taken together, these factors provide an extremely versatile platform that can target and treat a range of human diseases. This is what has enabled Inovio to investigate multiple therapeutic areas simultaneously.

The DNA medicine plasmid technology is coupled with a smart delivery device that improves plasmid uptake and, subsequently, increases immunogenicity. The Cellectra device is responsible for improving DNA plasmid uptake into cells and is among the major advances in DNA medicines over the past decade. Prior to the use of the device, DNA plasmids, upon injection into the muscle or  intradermal space, were less likely to be taken up by the cell, which prohibited their subsequent translation into suitable immunogenic proteins. But with the device, Inovio has used in vivo study results to demonstrate that immunogenicity can be increased 1000-fold, secondary to the ability for Cellectra to empower cells to take up the DNA plasmids and thereby translate their contents into viable antigens for the immune system to recognize.

Glioblastoma (GBM), or grade IV astrocytoma, remains in the majority of cases an incurable and devastating disease. The disease originates from the supportive glial cells of the brain, and patients present at diagnosis with diff use disease that has locally spread throughout the cerebral cortex, even if radiographically appearing isolated.  

Presentation can be sudden; common signs include headaches, ataxia, changes in speech or motor movements, and seizures. Although  surgery is the initial recommended therapy, not all patients can undergo optimal or complete resection, depending on where in the brain the tumor is located.

Surgery is almost always followed by radiation and chemotherapy, usually with temozolomide; this standard was set 15 years ago

 and has changed very little since. At that time, temozolomide, when added to standard-of-care radiation, provided a median overall survival of 14.6 months, an advantage of 2.5 months over radiation alone. A slight but significant prolongation has been seen in patients who use the tumor-treatment fi eld device Optune, but this improvement is about 3 months.

Several treatments have recently made their way to the clinic in an effort to harness the power of the human immune system to treat GBM. Many of these therapies aim to create a robust response to GBM. These include protein- or peptide-based vaccines; ex vivo manipulated immune cells, including chimeric antigen receptor T cells, which have been used in certain blood cancers; and checkpoint inhibitors, which been successful in treating multiple blood and solid tumor cancers. Unfortunately, several randomized studies of PD-1 receptor inhibitors have failed to demonstrate a clinical benefit in GBM to date.

 As such, patients with GBM continue to await a new therapy that can leverage or improve upon an immune response to GBM.

Inovio has developed INO-5401, a DNA medicine that is made up of 3 synthetic DNA plasmids encoding for human telomerase, Wilms Tumor 1 protein, and prostate-specific membrane antigen (PSMA). The company recently announced clinical data evaluating the percentage of patients alive at 12 months following their first dose of the DNA medicine candidate. INO-5401 was given with INO-9012, a synthetic DNA plasmid encoding for human interleukin-12, and with cemiplimab, a PD-1 inhibitor from Regeneron.

 In this 52-patient study, approximately 85% of patients were alive at 12 months, a potential improvement above historical controls (

Importantly, an immune response was seen in a majority of patients tested. In addition, evidence of an antigen-specific T-cell population that was activated and primed to kill GBM cells was identifi ed by both ELISpot and by flow cytometry. These novel therapies—INO-5401 and INO-9012 plus cemiplimab—were able to be given with both radiation and temozolomide chemotherapy. Reported adverse events were consistent with the known tolerability profile of the individual study drugs as well as with radiation, temozolomide, and the disease under investigation.

Previous research had demonstrated that more patients were  progression-free at 6 months than when compared with historical controls.

 Together, these promising, albeit early, clinical data  provide hope that Inovio’s novel DNA medicines have the potential to extend overall survival in patients with GBM. Additional survival results of this study will be available toward the end of 2020.

Although it has taken more than a decade, DNA medicines are now ready for success not only against infectious diseases and  precancerous conditions such as HPV-related cervical dysplasia, but against some of the deadliest diseases, such as GBM. With Inovio’s INO-5401 offering hope for patients with a fatal prognosis, there is the promise that technology can transform the treatment of GBM while improving quality of life and, ultimately, extending life.

Jeffrey Skolnick, MD, is vice president of clinical development, Inovio.

1. Kutzler MA, Weiner DB. DNA vaccines: ready for prime time? Nat Rev Genet. 2008;9(10):776-788. doi:10.1038/nrg2432

2. DNA medicines explained. Inovio. Accessed July 13, 2020. https://www.inovio.com/dna-medicines-technology/#explained

3. Inovio announces positive interim phase 1 data for INO-4800 vaccine for COVID-19. News release. Inovio; June 30, 2020. Accessed July 13, 2020. http://ir.inovio.com/news-releases/news-releases-details/2020/Inovio-Announces-Positive-Interim-Phase-1-Data-For-INO-4800-Vaccine-for-COVID-19/default.aspx

4. REVEAL 2 Trial (Evaluation of VGX-3100 and Electroporation for the Treatment of Cervical HSIL). ClinicalTrials.gov. Updated July 2, 2020. Accessed July 13, 2020. https://clinicaltrials.gov/NCT03721978

5. Lin F, Shen X, Kichaev G, et al. Optimization of electroporation-enhanced intradermal delivery of DNA vaccine using a minimally invasive surface device. Hum Gene Ther Methods. 2012;23(3):157-168. doi:10.1089/hgtb.2011.209

6. Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: prospects for success. Curr Opin Immunol. 2011;23(3):421-429. doi:10.1016/j.coi.2011.03.008

7. Stupp R, Mason WP, van den Bent MJ, et al; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996. doi:10.1056/NEJMoa043330

8. Optune patient website. Accessed May 18, 2020. https://www.optune.com

9. Bristol-Myers Squibb provides update on phase 3 Opdivo (nivolumab) CheckMate-548 trial in patients with newly diagnosed MGMT-methylated glioblastoma multiforme. News release. Bristol-Myers Squibb; September 5, 2019. Accessed July 13, 2020. https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-providesupdate-phase-3-opdivo-nivolumab-

10. INO-5401 and INO-9012 Delivered by Electroporation (EP) in Combination With Cemiplimab (REGN2810) in Newly-Diagnosed Glioblastoma (GBM). ClinicalTrials.gov. Updated July 9, 2020. Accessed July 13, 2020. https://clinicaltrials.gov/ct2/show/NCT03491683

11. Reardon DA, Brem S, Desai AS, et al. INO-5401 and INO-9012 delivered intramuscularly (IM) with electroporation (EP) in combination with cemiplimab (REGN2810) in newly diagnosed glioblastoma (GBM): interim results. J Clin Oncol. 2020;38(15 suppl; abstr 2514). doi:10.1200/JCO.2020.38.15_suppl.2514

12. Reardon D, Nagpal S, Soltys S, et al. Abstract CT114: INO-5401 and INO-9012 delivered by electroporation (EP) in combination with cemiplimab (REGN2810) in newly-diagnosed glioblastoma (GBM) (NCT03491683). Society for the Immunotherapy of Cancer (SITC) 2019 Annual Meeting; National Harbor, Maryland; November 6-10 2019. doi:10.1158/1538-7445.AM2019-CT114

Better technology is rekindling the promise of DNA medicines in oncology, including the treatment of glioblastoma.

How DNA Medicines Could Transform Treatment of Glioblastoma Multiforme

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

MEDICAL WORLD NEWS / Regulatory

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.

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

August 2020

Where Myths Go to Die

Second-Generation BTK Inhibitors Hit the Treatment Bullseye With Fewer Off-Target Effects

Partnership to Find Patients With NRG1 Fusions for Zenocutuzumab Trial in Pancreatic Cancer

How DNA Medicines Could Transform Treatment of Glioblastoma Multiforme

FDA Actions Include Third CAR T-cell Therapy

Best Cancer Tests Don't Reach All Who Need Them

MRD, Biomarkers in Multiple Myeloma

Sidebar: CMS Seeks to Fix Medicaid Best-Price Barriers in Value-Based Contracting for High-Cost Therapies in Medicaid

Hospitals Vow to Fight Court of Appeals 340B Ruling

Rethinking Downside Risk Protection Amid Growth in Precision Medicine

Don't Delay Cancer Care During COVID-19 Crisis

Choice Is Vital to Biosimilar Savings Picture, Panelists Say

Tafasitamab Combination Approved for Adults With R/R DLBCL