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

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

Several trastuzumab bioimilars have been launched this year, and 6 FDA-approved adalimumab biosimilars are lined up for launch in 2023, but a cornucopia of lower-cost therapies is not looked upon by providers as favorably as might be expected. 

The reason? Payer policies make it diffi cult for providers to use the lowest-cost biosimilars available. In a webinar hosted on July 20, 2020, by 

® and The Center for Biosimilars®, a panel of experts discussed how industry dealmaking is aff ecting treatment decisions and the use of resources at the provider level.

FDA-approved biosimilars are not diff erent from reference products in any clinically meaningful way. However, for business reasons, a payer may put a particular biosimilar on formulary because of a rebate it received from the manufacturer or high-pressure sales tactics used by a rival drug producer. Often, this means that providers must use the biosimilar that the payer requires—not the lowest-cost drug. For practices that work with multiple payers, each with diff erent biosimilar preferences, this can be “a nightmare,” panelists said.

 clinical coordinator of  hematology/oncology for The University of Arizona Cancer Center in Tucson; 

chief operations offi cer for Pontchartrain Cancer Center, with locations in Covington and Hammond, Louisiana; and 

, the pharmacist evidence analyst and strategist for hematology/oncology at Kaiser Permanente, based in Oakland, California. 

 senior vice president, Clinical Communications, of MJH Life Sciences, served as moderator.

The Difficulty of Stocking Multiple Biosimilars

Stocking multiple biosimilar brands to satisfy the preferences of multiple payers is costly, and ensuring that payer preferences are followed requires the use of controls and staff  interventions that would not ordinarily be needed for treatment decisions. “There’s a lot of work by nurses, pharmacists, and fi nance people to transition to biosimilars,” McBride said.

Financial risk is possible, too, for a practice that uses the wrong biosimilar brand and cannot get reimbursed for it, said Oubre. Her practice has implemented a signoff procedure to ensure that the preferred drug is given to a patient.

“Payers are really taking an active stand in dictating the drugs we use,” she said. Payer preferences make it difficult for a medium-size practice like Pontchartrain to provide biosimilars to patients. “It presents a lot of operational challenges.”

In his ideal scenario, McBride said, payers would not decide what biosimilars could be used. The United States would follow a European-style model in which the preferred or recommended biosimilar is the lowest-cost biosimilar available. In Denmark, for example, a biosimilar company will win a tender contract to provide a biosimilar for a 12-month period, after which the bidding process will reopen.

This not only lowers costs, explained McBride, but also shortens the amount of time needed to transition a patient to a biosimilar. In the United States, the process of getting a patient set up with a biosimilar is much more complicated on many levels. “We’re constantly working to address these pieces,”

McBride said. He added that achieving biosimilar access equality, or “parity,” across drug brands is crucial to realizing the true promise of biosimilars. “I would love to see more of a European model,” he said.

“Parity would be great,” Oubre agreed. “We believe in the science of biosimilars and the cost savings, and at the end of the day we all know that term, cost toxicity, and it’s not going away.”

Kaiser Permanente is a combination payer and medical group conglomerate that has, through its leverage, been able to achieve very high levels of biosimilar uptake, specifically by singling out a single biosimilar for coverage in different classes of medicine. “Kaiser has a unique structure,” said Chiu. “We have tried to focus on 1 product; it reduces operational challenges.”

Chiu acknowledged that at the provider level there are complexities that affect whether patients can receive the lowest-cost biosimilar, but said that Kaiser Permanente has worked to overcome these issues.

However, the emphasis on a single biosimilar makes it simpler to achieve large-scale buy-in, Chiu added. There’s an education component to building confi dence among providers and patients that can be accomplished with a streamlined approach.

“There are still a lot of misconceptions about biosimilars, and people are uncomfortable about switching despite all the data,” he said.

Practices attempt to discuss biosimilar choices with payers so that restrictions can be relaxed, with varying degrees of success. McBride described “a lot of pushback” from payers, and Oubre said that in her experience, “some are more receptive, some are not.”

With regard to the education component, McBride said that biosimilar education itself has to be defi ned. This could take many forms. For example, providers and patients would benefit from more real-world information about biosimilars as well as further studies, particularly ones that would elucidate the value of switching from originator drugs to biosimilars in order to extend the benefits of therapy. “We need more data to have this discussion,” he said.

Good pharmacovigilance will be an important way to add to this critical information pool, Chiu emphasized. 

Education could include information about oncology models of care, such as Oncology Care First, the CMS successor to the Oncology Care Model, McBride said. It’s important to know how biosimilars are going to help achieve the savings that these models are supposed to achieve, he noted.

Kaiser Permanente has sought to give providers educational materials on biosimilars, which have included clinical data on individual biosimilars investigated in particular settings. This has helped to achieve “buy-in,” Chiu said.

Oubre said she has not witnessed any information on biosimilars distributed by payers, and McBride said nonbranded biosimilar information would be useful.

One group that wants more information about biosimilars is employers, Oubre pointed out. “Employers really want to know more,” she stressed. “If something goes on formulary and a patient with breast cancer is switched and gets upset, an employer doesn’t want that.” 

Tony Hagen is senior editor for The Center for Biosimilars®.

The challenges of complying with payer mandates in biosimilars were discussed in a webinar sponsored by The American Journal of Managed Care® and The Center for Biosimilars®.

Choice Is Vital to Biosimilar Savings Picture, Panelists Say

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.

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.

MEDICAL WORLD NEWS / Managed Care

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

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.

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

August 2020

Where Myths Go to Die

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

Choice Is Vital to Biosimilar Savings Picture, Panelists Say

FDA Actions Include Third CAR T-cell Therapy

Best Cancer Tests Don't Reach All Who Need Them

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

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

Rethinking Downside Risk Protection Amid Growth in Precision Medicine

MRD, Biomarkers in Multiple Myeloma

How DNA Medicines Could Transform Treatment of Glioblastoma Multiforme

Hospitals Vow to Fight Court of Appeals 340B Ruling

Tafasitamab Combination Approved for Adults With R/R DLBCL

Don't Delay Cancer Care During COVID-19 Crisis