OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

The introduction of biosimilars is having a growing impact on breast oncology, as these agents move from supportive care to active treatment settings. As more patents for costly biologics have expired, biosimilars are expanding patients’ access to novel treatments at significantly reduced cost. For patients with HER2-positive breast cancer, the FDA has approved 5 trastuzumab biosimilars: Ogivri (trastuzumab-dkst), approved 2017; Herzuma (trastuzumab-pkrb), approved 2018; and Kanjinti (trastuzumab-anns), Ontruzant (trastuzumab-dttb), and Trazimera (trastuzumab-qyyp), approved in 2019 (

Table. Breast Cancer Indications for Biosimilar Versions of Trastuzumab (Herceptin)

Although biosimilars have been shown to be safe and effective—with more than a decade’s worth of data to support their use—numerous hurdles to their adoption in clinical practice remain.

, a panel of hematology-oncology experts discussed some of the challenges surrounding the integration of biosimilars in clinical practice using the breast cancer landscape as a prime example. These hurdles include the need for better education about these agents, including improved understanding of guideline recommendations and improved clarity on how to select between available options. They also shared insights on the feasibility of extrapolating data for these agents, whether these agents can be used interchangeably, and future developments that have the potential to reshape the biopharmaceutical sector.

The panelists emphasized the need for health care providers in the United States to be better informed about biosimilars, as these agents are still relatively new in the US oncology marketplace, especially outside of the supportive care setting. Subsequently, they said many misconceptions exist that may be limiting the use of these agents. “The first thing is that [a biosimilar is] not a generic. It’s not a small molecule that can be manufactured simply and repetitively like photocopying something. I’m being a little hyperbolic, but [making generics is] simpler than making a biologic in a living organism,” said Lee S. Schwartzberg, MD, who encouraged health care providers to familiarize themselves with the regulatory process for biosimilars, which is different than that for their originators.

“We were already used to incorporating biosimilars into the treatment management of breast cancer patients,” Schwartzberg said, noting the difference being that most of biosimilars were used in the supportive care setting. “Some physicians have taken a different approach to a supportive care medication as opposed to a therapeutic medication, where the outcome is truly potentially lifesaving. The stakes are high for the use of a drug like trastuzumab where it has such critical value in HER2-positive breast cancer.”

Schwartzberg said that while he feels comfortable using biosimilars because he trusts the FDA’s approval process, there is an information gap concerning their effect on long-term clinical outcomes. “A clinical trial population is different from the real-world patients who get the drug. So monitoring these patients, particularly now that we have an electronic health record system that enables us to aggregate data and obtain good outcomes information, will be particularly important,” he said.

In clinical practice, guidelines are often used to facilitate evidence-based treatment decision-making. The panelists explained that the National Comprehensive Cancer Network (NCCN) guidelines have started to incorporate biosimilars into their recommendations, an action that recognizes the value of having less expensive drugs that achieve comparable outcomes to their more expensive counterparts. For example, the NCCN breast cancer guidelines enable substituting an FDA-approved biosimilar for trastuzumab whenever trastuzumab is indicated, but they do not advocate for the use of any specific biosimilar over another.

 “It’s going to be agnostic because it’s really going to depend on the payer mix in the part of the country [where the biosimilar is being prescribed],” said Adam M. Brufsky, MD, PhD.

Schwartzberg said in his practice they have also written their own guidelines to facilitate use of biosimilars. “Because some patients are still using the originator product, it’s been a little more complex because we’ve had to keep both agents in use simultaneously,” he said. He also noted the same challenge as Brufsky: Different insurers mandate use of different drugs. “This has added a tremendous amount of complexity in community oncology and cost to the system, which one could argue is not value based in the general term because stocks of various drugs need to be maintained based on the insurer that the patient has,” he said.

Subsequently, Schwartzberg said it is important for health care providers to know which drugs they will get reimbursed for before prescribing any agent. “Even though we’re very confident that any of them would work, we would like the ability to pick which drug we use. But that’s not the system we live in today,” he said.

The panelists also examined the issue of interchangeability—whether one agent can be substituted for another, including changing a patient from the originator biologic to a biosimilar. Kashyap Patel, MD, said in his practice he tries to put all his patients on a biosimilar. “I’m very comfortable saying that if a biosimilar is approved, if it’s covered by the payer, if they’ve got the supply chain guaranteed, and if they have the appropriate patient assistance program, I’ll move them [to the biosimilar] right away,” he said.

Schwartzberg expressed a similar sentiment, adding that switching from an originator to a biosimilar also requires a discussion with the patient. “We ask the provider to talk to the patient and say, ‘We have another version of the drug you’re getting. It works just as good as the other one. It is highly similar in terms of its efficacy and its safety, but it will cost you less, it will cost us less, and we’d like to change you to that. Are you comfortable with that?’ And almost invariably we get, ‘Yes,’ ” he said.

The panelists noted that the mechanics of interchangeability vary between states, with some states having passed biosimilar substitution laws that govern substitution requirements, pharmacy notification requirements (ie, to prescriber, patient, others), and recordkeeping requirements. Thus, health care providers need to be familiar with the biosimilar substitution laws in their states before making substitutions. 

Although most states allow for substitutions if the FDA has determined a biosimilar to be interchangeable and a prescriber has not expressed a preference against the substitution, some states have additional stipulations. For example, Georgia also requires that patients approve the substitution and that the substituted biosimilar have the lowest retail price of all interchangeable biologics in stock when a prescriber prescribes a biologic by its nonproprietary name.

“Given the fact that [biosimilars have] undergone appropriate vetting from the FDA, I’m very comfortable that we could change to the biosimilar at the time it becomes available,” Patel said. “But there are some states where you may have to go through more bureaucratic nightmares. And, again, it’s one of those realities of life that we have to live with.”

Because multiple biosimilars are often available for one originator, selecting between them can be a challenge. However, Schwartzberg said the marketplace will help guide that decision. First, he said cost will come into play, particularly the reimbursement scheme for each biosimilar considered. Second, the reputation of the company should be considered. Third, it is important to select the agent that is less likely to run into delivery issues. “It’s thinking about the company that’s providing the drug—their reliability, their history, their experience with manufacturing biologics, and so forth,” he said.

Schwartzberg noted that even though not all state laws factor patients into the equation for biosimilar substitution or selection, it is important to consider patient preferences. Most patients are concerned with costs, so they should be offered the opportunity to switch to a biosimilar whenever possible. “It’s a tragedy that the most common reason for bankruptcy in the United States today is medical bills. And oncology, unfortunately, is one of the most expensive treatments out there. Every new drug that comes out now is over $100,000 a year, which is not sustainable,” he said, adding that when he tells patients there is a drug that is going to work just as well for them as what they are currently on but that it will cost them 30% less, most patients select the less costly option.

Although payers, providers, and patients are generally in favor of using biosimilars, Schwartzberg warned that payers sometimes have contracts that enable them to obtain the originator drug at a reduced cost. “It speaks to the complexity of the way drugs are reimbursed in the United States today. It’s something we’re living with and something that we’re trying to simplify and change,” he said.

Because biosimilars are not exact replications of their biologic counterparts, the panelists examined whether data for biologics could be extrapolated to biosimilars. Schwartzberg explained that extrapolation regarding biosimilars has a regulatory definition. “The regulatory definition from the FDA is that you do one clinical trial in a sensitive population so that you can pick up any differences between the originator and the biosimilar, and if you get a result that shows equivalence, you can extrapolate that data into other settings in the same disease,” he said, explaining that this also extends into any other approved indications for the originator drug.

Based on this concept, Schwartzberg said a biosimilar for a drug like trastuzumab, which has approval for HER2-positive breast cancer as well as HER2-positive gastric and gastroesophageal junction cancers, could be used in all these settings despite the biosimilars not being extensively tested outside of HER2-positive breast cancer. He said it also enables trastuzumab biosimilars to be used across breast cancer indications. “If you’re using a biosimilar that was tested in the neoadjuvant and adjuvant setting, it can also be used in the metastatic setting. I believe that any biosimilar can be extrapolated to any other indication that is in the FDA label,” he said.

Patel concurred: “I’m very comfortable with extrapolation because that’s one of the terms that the FDA has been fairly clear about.” However, he noted there are sometimes challenges to using biosimilars for all indications its originator has been approved for, citing use of bevacizumab-awwb (Mvasi) in the ovarian cancer space as an example. “The companies that have the competing product in the market have some sort of legal wrangling going on to ensure that that indication right now is not covered,” he said. Subsequently, the label for bevacizumab-awwb does not include ovarian cancer as an indication.

Schwartzberg said the only setting he would not be comfortable using a biosimilar is when there are no data to extrapolate. “I would be hesitant to use a biosimilar, just like I would be with the originator, in a nonindication situation, or at least where there have not been studies to date,” he said.

The panelists then discussed some emerging trends they suspect are going to impact the field of biosimilars in the future. For example, they noted the potential for biosimilar development to expand into other biopharmaceutical classes as more patents expire. “It’s possible we will have biosimilars in the realm of antibody-drug conjugates in the next few years,” Schwartzberg said.

Patel suggested the same about immuno-oncology (I-O) products. “When the I-O medications come off their patents in maybe 4 or 5 years from now, I think that we will probably look at all the different I-O compounds. I’m sure in 5 years, that probably will be another wave,” he said.

Another major development the panelists noted was the emergence of “biobetters,” which refer to drugs in the same class as an existing biopharmaceutical that are improved over their originators. “If you understand the biology and the manufacturing, potentially you could make a drug that works better [than the originator],” Schwartzberg said, explaining that biobetters would be a step up, not only in terms of less cost for the same efficacy, but maybe less cost for more efficacy—and that would be an exciting development.

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NCCN. Clinical Practice Guidelines in Oncology. Breast Cancer, version 5.2020. Accessed July 19, 2020. https://www.nccn.org/professionals/physician_gls/pdf/breast_blocks.pdf

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Mvasi. Prescribing information. Amgen Inc; 2019. Accessed August 3, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761028s004lbl.pdf

Articles

Features

During a recent OncLive Peer Exchange®, a panel of hematology-oncology experts discussed some of the challenges surrounding the integration of biosimilars in clinical practice using the breast cancer landscape.

Experts Decode the Future of Biosimilars in Breast Cancer

Although antibodies targeting inhibitory immune checkpoints have been central to the success of cancer immunotherapy in the past decade, evidence suggests stimulatory checkpoints are equally important in the generation of an effective antitumor response. Considerable efforts have focused on developing agonists of costimulatory receptors, including OX40.

The more nuanced role of these receptors and challenges inherent to developing agonist antibodies have proved significant stumbling blocks to clinical translation,

 but many pharmaceutical companies continue their pursuit in the hopes that new drug strategies will prove successful.

Data from ongoing clinical trials presented at recent conferences have highlighted several of these novel drugs and brought OX40 back into focus.

Full activation of naïve T cells requires not only interaction between the T-cell receptor (TCR) and major histocompatibility complex–bound peptides on the surface of an antigen-presenting cell (APC) but also a secondary signal provided by costimulatory molecules on the APC that bind to their  receptors on the T cell (

The prototypical costimulatory receptor, CD28, is expressed on naïve T cells and provides the initial costimulatory signal when bound to its ligand, but a range of other receptors and ligands are also upregulated in the hours and days after T-cell activation. These maintain T-cell activation and deepen the T-cell response by boosting proliferation and survival and optimizing the priming, differentiation, and effector functions of various T-cell subsets.

Among the costimulatory receptors is OX40, 1 of the 29 known members of the tumor necrosis factor receptor (TNFR) superfamily; 6 of these family members, including OX40, included are classified as immune costimulators.

 Expression of OX40 is upregulated on both CD4- and CD8-positive T cells between 12 and 24 hours after TCR engagement and is then gradually downregulated 48 to 96 hours later.

The only known ligand is OX40L, which is similarly transiently expressed on activated APCs. OX40L is also found on other cell types, including activated natural killer and B cells, as well as nonhematopoietic cells such as smooth muscle and endothelial cells. OX40 requires clustering for efficient activation. To facilitate this, OX40L contains conserved TNF homology domains through which it forms trimers that can bind to 3 OX40 receptor molecules simultaneously.

Like other TNFR superfamily members, OX40 is a transmembrane protein. Through its cytoplasmic tail, OX40 binds to members of the TNFR-associated factor (TRAF) family of adaptor proteins, specifically TRAFs 2, 3, and 5. TRAFs facilitate the activation of downstream signaling cascades, the best characterized being the nuclear factor kappa B (NFκB) pathway, ultimately eliciting a range of different effects in T cells, dependent on the specific subset.

Despite the success of immune checkpoint inhibitors (ICIs), many patients do not respond, and the development of resistance limits durable benefit for others. Costimulatory receptors have long been pursued as an alternative and potentially complementary target.

Preclinical studies have demonstrated the ability of agonistic OX40 antibodies to promote T-cell activation and enhance T-cell– mediated antitumor immunity, resulting in tumor regression and survival benefits across a variety of cancer models.

The first OX40 agonist to advance to clinical testing was 9B12, a mouse monoclonal antibody developed by the Providence Portland Medical Center and AgonOx, both in Portland, Oregon. The agent was subsequently renamed MEDI6469 when AgonOx in-licensed its OX40 program to MedImmune, an AstraZeneca company.

In a first-in-human study of 9B12/ MEDI6469 (NCT01644968), there were no tumor responses, although 40% of patients experienced regression of at least 1 metastatic lesion. Treatment was well tolerated, and there was significant evidence of immunomodulatory activity.

A humanized version of this antibody, MEDI0562 (tavolimab), was subsequently developed to prevent patients from forming human anti-mouse antibodies, which limited the number of doses in the above trial.

 In a phase 1 trial in patients with advanced solid tumors (NCT02318394), there were no dose-limiting toxicities (DLTs), and 1 patient exhibited a partial response (PR), which lasted 16 weeks.

 AstraZeneca has since discontinued development of MEDI6469 and MEDI0562,

 but the latter is still being studied by academic groups.

Two notable OX40 agonists, MOXR0916 and PF-04518600, were tested

; however, development of the former was discontinued completely in 2019,

 and the latter is no longer listed in Pfizer’s development pipeline.

 Overall, OX40 agonists as monotherapy have failed to live up to expectations, with only modest antitumor activity.

According to experts in the field, part of the problem lies in challenges inherent to developing agonist antibodies. Because antagonist antibodies exhibit a classic dose-response relationship, they are well suited to doseescalation studies. However, searching for the highest tolerable dose of receptor agonists has the potential to exhaust T cells and negate any antitumor efficacy.

Important considerations for designing optimal agonist antibodies include binding affinity, epitope selection, valency, and receptor occupancy. Furthermore, because costimulatory receptor clustering is key to the signaling activation induced by native ligand binding, an agonist antibody must be able to reproduce this effect.

Conventional bivalent antibodies, which can interact with only 2 receptors per antibody molecule, have low or no intrinsic agonist activity and are dependent on secondary cross-linking of antibody-receptor complexes caused by interaction between their Fc region and the Fcγ receptor (FcγR).

Despite setbacks, there is still considerable interest in pursuing OX40-targeted drugs (

), but the focus has shifted to combination therapy. The most popular strategy is to combine OX40 agonists with ICIs based on preclinical demonstration of synergy, although administering the drugs in the proper sequence can be a crucial consideration with these combinations.

Table. Select Studies of OC40-Targeted Drugs in Active Clinical Development

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GlaxoSmithKline is developing a humanized OX40 antibody, GSK3174998, which is being evaluated in several ongoing clinical trials in combination with different drugs. Results from the recently completed phase 1 ENGAGE-1 study (NCT02528357) were reported at the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting I.

Patients with advanced solid tumors were treated with escalating doses of GSK3174998 (0.003-10 mg/kg) intravenously every 3 weeks as monotherapy (part 1; n = 45) or in combination with 200 mg pembrolizumab (part 2; n = 96). In part 1, 1 patient had a PR and 1 achieved stable disease (SD), both at the 0.3 mg/kg dose. In part 2, there were 2 complete responses, 7 PRs, and 9 patients with SD at doses from 0.01 to 3 mg/ kg. Clinical benefit was observed in both PD-1/PD-L1 inhibitor–pretreated and treatment-naïve patients.

There were 2 DLTs in part 2 (grade 3 nonmalignant pleural effusion at 0.03 mg/kg and grade 1 myocarditis at 10 mg/kg). The most common treatment-related adverse events (TRAEs), which were predominantly grades 1 and 2, included diarrhea and fatigue in part 1 and fatigue and nausea in part 2.

To address the need for receptor clustering, modifying the Fc region of the antibody to enhance FcγR binding can be an effective strategy but can also boost several of the effector functions of antibodies, including antibody-dependent cellular cytotoxicity. Although this can be beneficial, providing an additional antitumor effect, it could also lead to depletion of the T cells activated by the costimulatory agonist antibody and thus diminish its antitumor immune effects.

An alternative strategy is to increase valency. Inhibrx is developing INBRX-106, a hexavalent OX40 monoclonal antibody that can bind 6 OX40 receptors per molecule of drug. It has been shown to outperform bivalent antibodies in preclinical testing, according to the company’s website.

Bispecific antibodies, designed to engage 2 different targets, also are under study. 

ATOR-1015 targets OX40 and the coinhibitory receptor, CTLA-4. A phase 1 first-in-human study (NCT03782467) in patients with advanced solid tumors is ongoing, and preliminary results were presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. ATOR-1015 was administered intravenously every 2 weeks at escalating doses from 0.043 to 600 mg. Patients were heavily pretreated, having received a median of 5 prior lines of therapy.

Data from 21 patients dosed to date demonstrated a best response of SD. There were no DLTs, and TRAEs were reported in 11 patients, most frequently infusion-related reaction and rash. No severe immune-related AEs were reported.

F-star Therapeutics is also developing FS120, a bispecific antibody that targets a second costimulatory receptor, 4-1BB (CD137), in addition to OX40. After promising preclinical trials,9 F-star announced in January that the FDA had accepted its investigational new drug application. A phase 1 dose-escalation trial is planned in patients with advanced malignancies, with anticipated enrollment of 70 patients.

Shattuck Labs is looking to achieve an effect similar to these bispecific antibodies via a different drug design. They used their Agonist Redirected Checkpoint platform to create SL-279252, a bifunctional fusion protein that consists of the extracellular domains of OX40L and PD-1 joined by a central Fc domain.

 A first-in-human clinical trial is ongoing (NCT03894618).

Nucleic acid–based drugs hold promise for gene therapy and could be used to induce tumor cells to express OX40L. These drugs present a challenge because naked genetic material is susceptible to degradation in the circulation, but lipid-based carriers offer a possible way around this problem.

Moderna Therapeutics is developing 2 messenger RNA (mRNA)-based drugs, mRNA-2416 and mRNA-2752, both composed of lipid nanoparticles encapsulating a synthetic mRNA encoding OX40L. mRNA-2752 also contains mRNAs encoding proinflammatory cytokines IL-23 and IL-36γ.

At the ASCO and AACR meetings, results from ongoing first-in-human studies of both drugs were highlighted. mRNA-2416 is being evaluated alone and in combination with durvalumab (Imfinzi) in patients with advanced solid tumors or lymphomas (NCT03323398). Results from the monotherapy arm were presented; as of November 2019, 39 patients with solid tumors had been treated with mRNA-2416 administered intratumorally every 2 weeks for up to 12 doses at 4 dose levels (1, 2, 4, and 8 mg). The best overall response was SD in 14 patients, including 4 of 6 patients with ovarian cancer. SD lasted for at least 14 weeks in 6 patients. Tumor shrinkage was observed in 7 patients, of whom 2 had shrinkage in injected lesions only, 3 in uninjected lesions only, and 2 in both lesion types.

There were no DLTs, and the majority of TRAEs were grade 1 or 2, most commonly fatigue and injection-related reaction. The combination of mRNA-2416 and durvalumab is being evaluated in the trial’s ongoing part B, which includes a dose-expansion portion focusing on ovarian carcinoma.

In a separate study (NCT03739931), intratumorally administered mRNA-2752 is also being assessed as monotherapy (arm A) and in combination with durvalumab (arm B) in patients with advanced solid malignancies or lymphoma. Patients receive escalating dose  of mRNA-2752 (0.25-8 mg) and a fixed 1500-mg dose of durvalumab. As of April 2020, 17 patients in arm A and 12 patients in arm B were evaluable for safety, and 15 patients in arm A and 8 in arm B were evaluable for efficacy.

In arm A, 5 patients experienced SD as best response; however, in arm B, 1 patient with PD-L1–low squamous cell bladder cancer had a PR and 4 patients achieved SD. Tumor shrinkage was observed in both injected and uninjected lesions in both study arms. TRAEs, which were predominantly grade 1 or 2, most commonly included injection site erythema, injection site pain, and pyrexia. Five patients in arm A experienced grade 3 TRAEs, but no grade 3 TRAEs occurred in arm B.

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Barba AA, Bochicchio S, Dalmoro A, Lamberti G. Lipid delivery systems for nucleic-acid-based-drugs: from production to clinical applications. Pharmaceutics. 2019;11(8):360. doi:10.3390/pharmaceutics11080360

Pathways

Considerable efforts have focused on developing agonists of costimulatory receptors, including OX40.

Fresh Approaches May Be Key to Unlocking OX40 Checkpoint

In early March 2020, the news reported a “superspreading” event in the town of New Rochelle, New York, a suburb with a Montefiore hospital that borders the Bronx where the flagship Montefiore hospitals are located. Soon after, in what seemed to be only possible in a dystopian fictional narrative, the National Guard arrived to assist with quarantining the area. We were told the source patient had no known sick contacts and no history of travel to a “hot zone.” I discussed with a colleague the catastrophic implications and potential for widespread disease dissemination. Within several days, the governor ordered, “New York State was on PAUSE,” which outlined the official closing plan, and Montefiore Health System was bracing for an onslaught of coronavirus disease 2019 (COVID-19) cases.

Early in the pandemic, it was clear that the risk posed to vulnerable populations exceeded that of the rest of the population. Patients with cancer would ostensibly be at higher risk of developing and succumbing to COVID-19 due to immunosuppression, increased coexisting medical conditions, and, in cases of lung malignancy, underlying pulmonary compromise. Patients with hematologic cancers, or those receiving active chemotherapy or immunotherapy, also might be particularly susceptible due to increased immunosuppression and/or dysfunction. 

Leadership at Montefiore Einstein Center for Cancer Care rapidly instituted measures to protect our patients while simultaneously attempting to avoid disruption to patients receiving ongoing cancer treatment. What complicated things further was that the virus causing COVID-19 infections had been circulating in our community for weeks. The effects were seen in our oncology clinics and COVID-19 wards.

As New York emerged as the pandemic epicenter in the United States, we felt it was our duty to report on the case-fatality rate within our oncology population to inform other health care systems, patients with cancer, and the public about oncologic patients’ particular vulnerability to this COVID-19.

A group of physicians from medical, radiation, and surgical oncology quickly banded together to gather data on COVID-19–infected oncology patients. We greatly benefited from existing databases that allowed us to rapidly identify and extract baseline data from our hospital system, which extends from New York City to upstate New York.

Early in the pandemic, the Montefiore hospital leadership had the forethought and insight to create a reliable and robust outcomes data collection system on all patients with a diagnosis of COVID-19 being seen and treated within the system. We were able to marry this data set with an existing database created to identify patients with cancer, and track treatment volumes and timelines of care in real time.

A total of 218 patients with cancer and COVID-19 infection from March 18 to April 8, 2020, were identified. The database included 164 (75%) patients with solid tumors and 54 (25%) with hematologic malignancies (

Sixty-one (28%) patients died from COVID-19 infections. The mortality rate was 25% of all patients with solid tumors. The highest rates of death occurred in patients with lung cancers (55%); gastrointestinal cancers, including colorectal (38%), pancreas (67%), and upper GI (38%); and gynecologic malignancies (38%). Genitourinary (15%) and breast cancers (14%) were associated with relatively lower mortality with COVID-19 infection. Hematologic malignancies were associated with higher case fatality rates (37%). Older age and comorbidities, such as concomitant heart disease—including hypertension, coronary artery disease, and chronic heart failure—and chronic lung disease, increased the risk of dying from COVID-19 in patients with cancer. 

Interestingly, active disease (< 1 year) and advanced metastatic disease showed a trend for increased mortality, but the association did not achieve statistical significance (

 = .06, respectively). Active chemotherapy and radiation therapy treatment were not associated with increased case fatality. 

An age and sex-matched cohort of 1090 patients at a 5:1 ratio of patients without cancer to patients with cancer and COVID-19 from the same time period and from the same hospital system also was obtained after propensity matching. This was used as a control to estimate the increased risk posed to our cancer population.

We observed case fatality rates that were elevated in all age cohorts in patients with cancer and achieved statistical significance in the age groups 45 to 64 (OR, 4.35) and in patients older than 75 years (OR, 2.83). We also compared our case-fatality rates with a larger data set from the greater New York City region, and in all age cohorts, patients with cancer demonstrated a striking increase in case-fatality rates (

A detailed analysis of patients who died (N = 61) demonstrated that many were either nursing home or shelter (n = 22) residents, and/or admitted as an inpatient or came to the emergency room within the 30 days prior to their COVID-19 positive test (n = 21). Altogether, 37 patients (61%) in the deceased cohort were exposed to the health care environment at the outset of the COVID-19 epidemic, thus emphasizing the need for early social-distancing efforts, resources for more outpatient-based care and telemedicine, testing of asymptomatic high-risk patients, and institution of strict infection control measures for our most vulnerable patients. By acting immediately upon our findings, we ensured that the appropriate and best care possible could be delivered to our patients.

Overall, our data suggested a significant risk posed to patients with cancer infected with COVID-19 with a measurable increase in mortality. The highest susceptibility appeared to be in hematologic or lung malignancies, suggesting that proactive strategies to reduce likelihood of infection and improve early identification of COVID-19 positivity are warranted in the population of patients with cancer.

In coming together to report on a large COVID-19–positive cancer cohort in the US epicenter, we were able to quickly translate our findings to clinicians and hospital professionals across the country. We also provided guidance to diminish the rate and consequences of this evolving infection in the vulnerable oncology population.

Our hope is that by reporting quickly on these data, lives of people with cancer can be spared. Our findings also inform cancer physicians on who could and should still be getting cancer treatment if precautions to separate people with cancer from others with COVID-19 infections are strictly followed. 

Mehta V, Goel S, Kabarriti R, et al. Case fatality rate of cancer patients with COVID-19 in a New York hospital system. 

. 2020;10(7):935-941. doi:10.1158/2159-8290.CD-20-0516

Partner Perspective

Early in the pandemic, the Montefiore hospital leadership had the forethought and insight to create a reliable and robust outcomes data collection system on all patients with a diagnosis of COVID-19 being seen and treated within the system.

A View From the Frontlines: How a Hospital System Coped With a COVID-19 Peak

Financial issues are among the top concerns burdening patients with cancer.

 Even with insurance, patients often face unpredictable costs, including high co-insurance and deductibles.

 The average annual cost of new medicines continues to trend upward, with the median cost at $149,000 in 2018.

 These high costs can lead to nonadhereance and drug abandonment.

At the same time, patients with cancer and facilities often throw away unused or leftover medications. In fact, according to a 2016 study in the British Medical Journal, an estimated $3 billion in leftover cancer drugs are discarded in the United States every year.

 This is especially true for medications that are based on a patient’s weight and that come in single-dose packages, which have to be discarded. 

One solution to address increased medication waste and access has been the use of drug repositories. So far, 38 states have enacted laws related to the donation and reuse of medication, and 20 states have operational programs.

 Laws in 13 states allow repositories to accept and distribute cancer prescription drugs, and 7 of these have operational programs (Table).

The American Society of Clinical Oncology supports the use of repositories as a way to lower costs and improve access to therapies for oral medications in a closed system.

Table. Operational Drug Repository Programs With Cancer Provisions

A drug repository is a program that receives eligible donated drugs that can then be provided to patients who have a financial need or who are patients of a nonprofit clinic, explained Julie Kennerly-Shah, PharmD, MS, MHA, BCPS, a pharmacist and associate director of pharmacy at the Ohio State University Comprehensive Cancer CenterJames Cancer Hospital (OSUCCC-James) in Columbus, Ohio. 

“There are varying rules from state to state as to which drugs are eligible to be donated to a drug repository program,” said KennerlyShah. “In Ohio, for example, we recently expanded to oral chemotherapy agents that had been in the possession of a patient. But we do not allow injectables.”

According to Doug Englebert, MBA, RPh, a pharmacy practice consultant, at the Wisconsin Department of Health Services, who is involved in the state’s drug repository program, pharmacies and clinics can sign up to participate in the program. “They get placed on our provider list and then any consumer or business can donate medications that fit the criteria, which usually means it’s in a package that’s tamper-evident sealed and that the medication still has viable life in it, so that means usually at least 90 days left on the expiration date,” he explained.

Englebert also noted that certain drugs cannot be used in the program, including controlled substances, such as morphine and high-risk medications that are part of federal monitoring programs. One example of this is lenalidomide (Revlimid), which is an oral medication for multiple myeloma. Because of the risk of birth defects, lenalidomide, a derivative of thalidomide (Thalomid), is monitored through an FDA-required Risk Evaluation and Mitigation Strategy. 

Some hospitals, such as OSUCCC-James, have coordinators who are dedicated to finding options for patients to access medications. Patients are evaluated for inclusion in manufacturer assistance programs or other sources that may help with medication costs. “Once we exhaust other options, the medication assistance coordinator would present this as an option to the team and to the patient to see if they would be interested in utilizing the drug repository,” Kennerly-Shah said.

In contrast, volunteer-based programs provide lists of participating facilities on a website, for example, from which patients can contact a facility to determine whether there is a need for a donation or whether a product is available that can be redistributed.

Large medical groups with multiple participating sites will often pool donations and designate a single site to manage the dispensing so that patients can more easily determine availability and access to medications in a particular geographic location.

“What they’re doing is packaging the medications in a way that can be tamper evident, they dispense these medications, and they tell the patients to donate them back if they become intolerant and discontinue medications,” Englebert explained. 

“In oncology, it’s very common for patients to change medications or have a dose reduction, and they end up with a surplus of medication that is quite expensive that another patient could significantly benefit from,” Kennerly-Shah said. 

OSUCCC-James worked with the Ohio Board of Pharmacy to create new rules allowing them to take medications that one patient cannot use into the drug repository program and then provide that drug to another patient who is in need, at no cost to that patient. Kennerly-Shah noted that to her knowledge, no donated medications have been deemed ineligible through the inspection process.

Drug repositories are resource-intense commitments. “You need pharmacists to inspect the medication,” Kennerly-Shah explained. “You need a place to store the medication safely. You need a process to identify who should be eligible to receive the donated drug. And then, of course, you need the resources to be able to actually redispense that drug to another patient.” 

Patients are required to have a prescription and records must be kept about the dispensing of any prescription drug.

Some states, such as Wisconsin, do not have a statewide central inventory of medications that are available in the repository program that practitioners or patients can access. Currently, practitioners and patients must connect with local facilities to determine medication availability. A local control model works in some environments, so there hasn’t been a push to evolve into a statewide initiative. There are other challenges as well. It’s often an unreliable source of medications for patients and their physicians.

“Practitioners never know if they will get the product and when they do, they need to have space to store it and it’s a separate inventory,” Englebert said. “It becomes a challenge on the management side a little bit.” 

Larger programs, such as Iowa’s SafeNetRx, have statewide support and a budget. They essentially manage all their medications and dispense out of there. This type of program is used differently than other programs across the country.

Oncologists who may be associated with a large health system or a large academic medical center may benefit from resources that are already in place at the health system to operationalize a repository program. However, smaller practices may experience difficulties due to the resource-intense nature of the process.

“The more patients you see, the higher likelihood that you have a large donation pool as well,” noted Kennerly-Shah. “So, one of the things that we thought very hard about when we were launching was which medications to start with,” she explained. They also considered which medications had a need and which medications had a surplus in the community in which they were likely to receive significant donations.

Kennerly-Shah noted that she hopes to expand to include every oral oncolytic and supportive care medication.

At OSUCCC-James, patients and their caregivers have expressed their gratitude for the opportunity to donate oral chemotherapy medications. Patients deciding to discontinue treatment and transition to hospice have been happy to give that medication to another patient with cancer.

“I’m always humbled by the camaraderie and the sense of oneness that I see from one cancer patient to another and a true desire to help others in the cancer community,” explained Kennerly-Shah. “I just am so impressed with our patient population and how much they’ve embraced this program and desire to help other patients that are going through a similar challenge in life."

Hendren S, Chin N, Fisher S. Patients’ barriers to receipt of cancer care and factors associated with needing more assistance from a patient navigator. J Natl Med Assoc. 2011 Aug; 103(8): 701-710. doi:10.1016/s0027-9684(15)30409-0

American Cancer Society. The costs of cancer care: addressing patient costs. Published April 2017. Accessed June 8, 2020. https://www.fightcancer.org/sites/default/files/Costs%20of%20Cancer%20-%20Final%20Web.pdf

The IQVIA Institute. Global oncology trends 2019. Published May 30, 2019. Accessed June 8, 2020

American Society of Clinical Oncology. Position statement on drug repository programs. Accessed June 8, 2020. https://www.asco.org/sites/new-www.asco.org/files/content-files/advocacy-and-policy/documents/2020-DrugRepositoryPositionStatement.pdf

Bach P, Conti RM, Muller RJ, et al. Overspending driven by oversized single dose vials of cancer drugs. BMJ. 2016;352:i788. doi.org/10.1136/bmj.i788

National Conference of State Legislatures. State prescription drug return, reuse and recycling Laws. Published October 1, 2018. Accessed May 7, 2020. http://www.ncsl.org/research/health/state-prescription-drug-return-reuse-and-recycling.aspx

Drug Repositories Aim to Solve Access Issues

The approval of tazemetostat (Tazverik) has expanded the portfolio of treatment options for relapsed/refractory (R/R) follicular lymphoma (FL), a disease for which new agents are needed because patients do not uniformly derive benefit from available therapies.

On June 18, 2020, the FDA granted an accelerated approval for tazemetostat for 2 distinct populations: Adults with R/R FL whose tumors are positive for an 

 mutation as detected by an FDA-approved test and have received at least 2 prior systemic therapies, and adults with R/R disease who have no satisfactory alternative treatment options.

 The drug initially was approved in January 2020 for adult and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.

The EZH2 inhibitor’s FL approval is based on overall response rate (ORR) and duration of response (DOR) data from cohort 4 and cohort 5 of the phase 1/2 E7438-G000-101 trial (NCT01897571) in patients with histologically confirmed FL who received a minimum of 2 prior systemic therapies. The efficacy cohorts comprised 42 patients with 

In cohort 4, the ORR was 69% (95% CI, 53%-82%), with a 12% complete response rate and a 57% partial response rate. The median DOR was 10.9 months. In cohort 5, the ORR was 34% (95% CI, 22%-48%), with a 4% complete response rate, a 30% partial response rate, and a median DOR of 13 months.

Continued approval for the FL indications may be based upon findings from a confirmatory phase 3 trial (NCT04224493) that is comparing tazemetostat in combination with the R

 regimen of rituximab (Rituxan) plus lenalidomide (Revlimid) versus R

 plus placebo in patients with R/R FL who have received at least 1 prior systemic therapy.

 The study, which has an estimated enrollment of 518 patients, will stratify patients based on their 

, Tycel J. Phillips, MD, medical oncologist and principal investigator of the E7438-G000-101 study site at the University of Michigan Rogel Cancer Center in Ann Arbor, discussed the advantages of tazemetostat for patients with FL.

: There was a very high ORR in patients with 

-mutant disease. The DOR in these patients was a bit shorter than what people would anticipate, but I think there are 2 parts to that, one being the slow enrollment in the EZH2-mutant cohort, which is still not as mature as the wild-type cohort.

-mutant disease were noted to have mild progression, which would have been pseudo-progression in some cases given that on subsequent scans, these same areas demonstrated interval reduction with further treatment. These patients were originally allowed to remain on study [because] they were still deriving benefit from tazemetostat. [However,] these patients were unfortunately impacted by [a temporary] FDA hold in 2018 and removed from the trial at the time of the hold. At our site, we had a few patients like this who were still benefiting from the trial, but were forced to come off study.

Another takeaway from this study is that the drug was also effective in patients with wild-type disease, who did have responses, although these responses were not as high as those in patients with the mutation. The DOR for patients with wildtype disease was fairly reasonable and comparable to some of the other agents that are currently approved in the third-line setting and beyond for follicular lymphoma.

Please describe tazemetostat’s safety profile.

Overall, tazemetostat was well tolerated. In the patients treated [at our site], the most commonly reported AEs [adverse events] were cytopenia (mainly thrombocytopenia) and gastrointestinal symptoms. The gastrointestinal symptoms are fairly common with most oral agents, but none of the cases were severe. Similarly, the cytopenias noted were mild. There were very few grade 3 or 4 AEs that led to treatment discontinuation.

In the third-line setting and beyond, tazemetostat has a very good safety profile compared with other agents approved in this setting.

The approval of tazemetostat has expanded the portfolio of treatment options for relapsed/refractory follicular lymphoma, a disease for which new agents are needed because patients do not uniformly derive benefit from available therapies.

Vol. 21/No. 16 | Oncology Live®

Experts Decode the Future of Biosimilars in Breast Cancer

Fresh Approaches May Be Key to Unlocking OX40 Checkpoint

A View From the Frontlines: How a Hospital System Coped With a COVID-19 Peak

Drug Repositories Aim to Solve Access Issues

Tazemetostat Expands Follicular Lymphoma Tool Kit

Chasing a Cure in Lung Cancer: Kris Urges Pushing Forward in COVID-19 Era

Biomarker-Driven Monotherapy Enters mCRPC Paradigm

It’s Time to Modernize Genetic Counseling in Oncology