Cracks in COVID-19 trials still showing

Many COVID-19 Trials Rife With Design Flaws

By David Wild

One problem that infectious disease physicians, pharmacists and other specialists had throughout the COVID-19 pandemic was accessing rigorous scientific data to guide clinical decision making. Such efforts were crucial to achieving at least some successful outcomes as case counts and mortality rates soared during the pandemic.

To this end, many clinical trials were started. However, not all had that scientific rigor, and findings were often contradictory, making it difficult for healthcare providers and public health officials to advise patients and families. Early in the pandemic, COVID-19 treatment trials were hampered by enrollment of small study populations, use of surrogate markers and open-label design, according to researchers from the Johns Hopkins University School of Medicine.

Since the beginning of the pandemic, more than 200 papers about COVID-19 have been retracted or withdrawn, and journals voiced concern about several others that have not been retracted, according to the website Retraction Watch.

An early study by investigators at Johns Hopkins, perhaps, sheds light on why so many papers have been retracted. In 2020, the Hopkins investigators looked at some of the early studies that focused on treatment (BMJ Open 2020;10:e039978). (The retracted papers are not just about treatment, but touch on a wide number of COVID-19 topics.)

The Hopkins study painted a picture of more than 200 disparate and disconnected trials carried out at dozens of sites around the world, leading to findings of limited clinical applicability.

“We understand the urgency of clinical research on COVID-19, but this is a time when we need rigorous science to inform policy and clinical decision making,” lead researcher Hemalkumar Mehta, PhD, told Infectious Disease Special Edition, a sister publication to Pharmacy Practice News, shortly after publishing the report in June 2020.

Dr. Mehta, an assistant professor in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health, in Baltimore, and colleagues scoured the World Health Organization’s clinical trials registry network as well as ClinicalTrials.gov, documenting studies registered up to March 26, 2020. They also searched major medical journals and other key websites that list clinical trials. The researchers found 201 clinical trials examining 92 drugs or convalescent plasma. Sixty-four trials studied monotherapy and 28 included a variety of treatment combinations. All but eight of the studies examined already-approved molecular entities.

According to Dr. Mehta’s team, 75.7% (152/201) of the trials included randomization to treatment or a comparator. Thirty-six percent (55/152) of the trials had some form of blinding and 97 were open-label studies.

Of the 24% (49/201) of studies that were not randomized, 29 were singlearm studies and 20 had one or two comparator arms, with only 10% of these multi-arm studies using a blinded design.

When they looked at the geographic

location of the trials, the researchers found that 49.8% (100/201) of the trials were registered in China, while 37.8% (78/201) were registered in the United States. More than half (110/201) of the studies were sponsored by hospitals or universities, 19.4% (39/201) were funded by governments, and the remainder were industry sponsored.

Although 66.7% of the trials (134/201) included one or more clinical end points—such as COVID-19 symptoms, death, recovery, need for intensive care or hospital discharge—the remainder used surrogate end points or biomarkers, most commonly looking at viral load. Roughly 27% (54/201) of the studies aimed to enroll 50 or fewer patients, while 46.8% (94/201) had the goal of enrolling 100 or more patients.

“Poor trial designs, lack of hard clinical end points and small trials may limit usefulness of data in guiding clinical practice,” said Dr. Mehta, noting the number of trials studying COVID-19 treatment increased since they conducted their analysis. As of early January 2022, there were more than 7,300 registered studies about COVID-19 with ClinicalTrials.gov, but not all were examining drugs or plasma.

“Since our study, government and pharma sponsorship of these trials has also increased, which will make trials more collaborative, bigger and hopefully with better-designed elements,” he said.

A Pharmacist’s Take

C. Michael White, PharmD, the head of the Department of Pharmacy Practice at the University of Connecticut School of Pharmacy, in Storrs, acknowledged that although the research and clinical community did not have the luxury to wait for conclusive studies during the early days of the pandemic, the community “could have done research so much better if we had a true pandemic response infrastructure in place. Instead, everyone did their own thing instead of running a logical cluster randomized trial, in which some sites would have looked at standard of care and others studied standard of care plus a set number of different interventions,” explained Dr. White, who was not involved in the Hopkins study but is no stranger to medical research, having published more than 410 peer-reviewed publications during his pharmacy career.

Using such a standard-of-care lens in COVID-19 research would have led to a balanced data set and more reliable but still rapid results, he said. “Unfortunately, by generating a bunch of highly biased, heterogeneous and underpowered studies, [many COVID-19 study] results have been wildly contradictory,” Dr. White stressed.

Aaron E. Glatt, MD, the chair of the Department of Medicine at Mount Sinai South Nassau, in Oceanside, N.Y., had a different perspective. Although there are “a tremendous number of differences in the studies, the critical and heartening thing is that there are so many studies underway looking at so many different interventions, both old and new,” he said.

Although some studies were not very helpful, “you just need one or two trials to make a dramatic impact on the management of COVID-19, if they are well designed and find a treatment is useful,” said Dr. Glatt, who was not involved in the research.

Troubling Numbers

24% of studies were not randomized

29% were single-arm studies

Only 10% of the multi-arm studies were blinded >1/3 of the trials used surrogate clinical end points or biomarkers

Source: BMJ Open 2020;10:e039978.

‘You just need one or two trials to make a dramatic impact on the management of COVID-19, if they are well designed and find a treatment is useful.’ —Aaron E. Glatt, MD ‘Unfortunately, by generating a bunch of highly biased, heterogeneous and underpowered studies, [many COVID-19 study] results have been wildly contradictory.’

—C. Michael White, PharmD

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CAR-T Therapy Insights

continued from page 1

treatment choice in these challenging malignancies, experts noted.

CAR T-Cell Therapy Versus Standard of Care

ZUMA-7

Of several studies presented on CAR T cells at the ASH meeting, two involved trials in relapsed or refractory (R/R) lymphoma. One, ZUMA-7, found axicabtagene ciloleucel (Yescarta, Kite) more effective than the current standard of care (SOC) for R/R large B-cell lymphoma. However, a much anticipated second trial, called BELINDA, failed to show an advantage for tisagenlecleucel (Kymriah, Novartis) over SOC in R/R aggressive non-Hodgkin lymphoma (aNHL).

Not deterred by the results of the BELINDA trial, Laurie Sehn, MD, the chair of the Lymphoma Tumor Group, British Columbia Cancer Agency, in Vancouver, is convinced that the “remarkable” overall data with CAR T cells will exert an enormous impact on clinical practice. Indeed, she said it is “inevitable” that CAR T-cell therapy will become the SOC in advanced forms of lymphoma.

In the multinational ZUMA-7 trial (abstract 2), 359 patients with R/R large B-cell lymphoma were randomized to a single infusion of axicabtagene ciloleucel or SOC. Axicabtagene ciloleucel was administered after completing the multistep process that involves conditioning of the patient’s own T cells, leukapheresis, T-cell engineering and reinfusion. SOC consisted of two to three cycles of investigator-selected but protocoldefined platinum-based chemotherapy (PCT) regimens. In the case of lack of response to SOC, crossover to CAR T cells was permitted.

On the primary outcome of event-free survival (EFS), the hazard ratio (HR) translated into a more than 60% relative advantage (HR, 0.398; P<0.0001) after two years of follow-up. The median EFS was 8.3 months in the CAR T-cell arm versus 2.0 months on SOC. The greater median overall survival (OS; HR, 0.730; P=0.027) for the CAR T-cell arm did not reach a predefined level of significance, but the objective response rate (ORR) did (83% vs. 50%; P<0.0001). These differences were observed despite the fact that 56% of the SOC arm eventually received off-protocol CAR T-cell therapy.

Treatment-related deaths occurred in one patient in the CAR T-cell arm and two patients in the SOC arm. Grade 3 or higher cytokine release syndrome was observed in 6% of patients.

The side effects of this CAR T-cell regimen were “manageable,” noted lead investigator Frederick Locke, MD, the vice chair of the Blood and Marrow Transplant and Cellular Immunotherapy Department, Moffitt Research Center, University of South Florida, Tampa. He indicated that the data support CAR T-cell therapy as a new SOC in R/R large B-cell lymphoma.

BELINDA

In the phase 3 BELINDA trial (abstract LBA-6), 322 patients with R/R aNHL were randomized to a single infusion of tisagenlecleucel or an investigator choice of protocol-defined PCT regimens. The PCT was followed by hematopoietic cell transplant (HCT) in responders or a second best-choice regimen in nonresponders. Patients were eligible for the study if they failed to respond or relapsed within 12 months of first-line therapy.

At three months, the median EFS, which was the primary end point, was exactly the same in the two study arms. The ORR was only slightly greater in the CAR T-cell arm (46% vs. 43%).

In the study design, patients in the CAR T-cell arm were permitted to receive an optional bridging treatment with one of the protocol-defined PCT regimens followed by lymphodepletion. This bridging led to an inherent delay in CAR T-cell delivery, according to principal investigator Michael R. Bishop, MD, the director of the Hematopoietic Stem Cell Transplantation Program at University of Chicago Medicine. He considers this one potential explanation for the negative result.

Dr. Bishop stressed that the trial, although negative, offers important insights that “will inform use of cellular therapy in the second-line R/R aNHL setting [and] guide future CAR-T trials.”

Off-the-Shelf Treatments

As noted, autologous CAR T-cell therapy can be subject to supply challenges, given the variability of patients’ T-cell yields. The agents also have special storage requirements. Thus, off-the-shelf allogeneic treatments that use conventional targeted chemotherapy approaches can be viable alternatives. Valemetostat tosylate is one such agent, and was associated with highly encouraging activity in a small but pivotal trial that enrolled patients with R/R adult T-cell leukemia/ lymphoma (ATL) (abstract 303).

In a highly pretreated population, of which nearly all (96%) had received mogamulizumab-kpkc (Poteligeo, Kyowa Kirin), ORR was 48%, with 20% achieving a complete response to valemetostat.

In addition to the high rates of activity, eight of the 25 patients are still deriving benefit and remain on therapy after a median of 28 weeks of followup, the investigators reported. The median duration of remission has not yet been reached in a population that had few treatment options, the investigators said.

Grade 3 or greater treatment-related adverse events occurred in 15 (60%) of the 25 patients enrolled, but only two discontinued treatment due to adverse events. The most common adverse events were thrombocytopenia, dysgeusia, anemia and alopecia, which was observed in 40% of patients, but these were manageable, according to to the researchers.

As for the agent’s key mechanisms of action, valemetostat targets the enhancer of zeste homolog 1 and 2 (EZH1 and EZH2), which are implicated in the epigenetics of T-cell leukemia/lymphoma proliferation. Evidence that this is a clinically important and viable target of disease control was derived from a phase 1 trial (abstract S218) of patients with R/R NHLs, including peripheral T-cell lymphoma (PTCL), ATL and other cancers, presented at the European Hematology Association 2021 Virtual Congress.

Despite the limited size of the current study, the data have been submitted to regulatory authorities in Japan. Further studies are planned, according to the researchers, including a pivotal phase 2 study known as VALENTINE-PTCL01. The trial will assess the safety and efficacy of valemetostat in patients with R/R PTCL and ATL (ClinicalTrials.gov Identifier: NCT04703192).

A Hematology/Oncology Pharmacist’s Take

In treatment-experienced patients with advanced lymphoma, the top concern for many pharmacists is managing the adverse events, according to Aseala I. Abousaud, PharmD, a lymphoma clinical pharmacy specialist in the Winship Cancer Institute of Emory Healthcare, in Atlanta. Focusing on the expanding role of CAR T-cell therapy in R/R lymphoma, she urged pharmacists to stay current with risks as well as efficacy.

“I do believe pharmacists will be playing a major role in CAR T-cell therapy, especially in the prevention and management of side effects,” Dr. Abousaud said.

The proportion of cancer centers already offering this option has been growing steadily. Promising results with off-the-shelf products suggest that it might soon be possible to offer CAR T-cell therapy to a much larger population. On this basis, Dr. Abousaud recommended that pharmacists who are active in programs with substantial cases of R/R lymphoma need to understand the differences in the risks of the expanding number of CAR T-cell products as well as their relative ability to extend survival.

Autologous CAR T-cell therapy must be stored in liquid nitrogen; off-the-shelf options have no such requirements.

Source: David Caulfield, the Pharmaceutical Journal.

More Leukemia/Lymphoma News on the Web

Managing Asparaginase Hypersensitivity Reactions bit.ly/36aglhj

Studies Point to Optimal Dosing in Acute Leukemia And Lymphoma bit.ly/34lMn9g

Another Off-the-Shelf CAR-T Therapy Shows Promise bit.ly/3rGnj60

Dr. Abousaud reported no relevant fi nancial disclosures. Dr. Bishop reported fi nancial relationships with Arcellx, Autolus, Bristol Myers Squibb, Kite and Novartis. Dr. Locke reported fi nancial relationships with GammaDelta, Iovance, Janssen, Kite, Novartis and Umoja. Dr. Sehn has fi nancial relationships with AbbVie, Amgen, Apobiologix, AstraZeneca, Debiopharm, Genmab, Gilead, Incyte, Janssen, Karyopharm, Kite, Lundbeck, Merck, Morphosys, Novartis, Roche/Genentech, Sandoz, Seattle Genetics, Takeda, TG Therapeutics and Verastem.

Tech helps risk-stratify pediatric leukemia patients

Is It Time for Next-Generation Cancer Sequencing?

By Ted Bosworth

By accurately assessing minimal residual disease (MRD) status, next-generation sequencing (NGS) is showing promise for improving the risk stratification of pediatric patients with newly diagnosed acute lymphoblastic leukemia (ALL), according to a multicenter study (abstract 618) presented at the 2021 annual meeting of the American Society of Hematology (ASH).

Unlike current assays such as flow cytometry (FCM), NGS assays employ unique genetic sequences in leukemia cells “to detect MRD at the level of 12 leukemic cells in 1 million cells,” according to Jonathan D. Paolino, MD, a pediatric hematology/oncology fellow at Dana-Farber Cancer Institute, in Boston, and a study co-investigator.

The multicenter study included 317 children being treated on the DanaFarber Cancer Institute ALL protocol. When compared with FCM, which was also performed, NGS identified a higher proportion of cases with high MRD status, Dr. Paolino reported.

“The majority of discrepant cases were just above the FCM limit of detection,” he said.

In this series, NGS was used as the primary method of MRD-based risk determination. FCM was employed as a backup. Initial bone marrow evaluations were performed at the time of diagnosis and four weeks after induction therapy, identified as the first time point (TP1).

Patients with a high MRD, identified as

equal to or greater than 1 leukemic cell per 10,000 cells (10-4), received intensified therapy and additional MRD assessments after 10 and 20 weeks of therapy.

Patients from the age of 12 months through 21 years with B- or T-cell ALL were eligible for inclusion. Most (84%) had B-cell ALL and were less than 10 years of age (67%). When determined on the basis of age, baseline leukocyte count, central nervous system leukemia status, immunophenotype and disease biology, 52% were identified as low risk, 31% as high risk and 17% as very high risk.

Among 70 B-ALL patients with high MRD, 43% (n=30) were high by NGS (≥10-4) when FCM was low (<10-4; n=4) or undetectable (n=26), with 90% of discrepancies at the NGS level of 10-4. In contrast, among 28 T-ALL patients with high TP1 MRD, 75% (n=21) were high by NGS alone, all with undetectable FCM, according to the study.

“Sixty-seven percent of these patients had NGS MRD at the level of 10-4 and the remaining 33% were in the range of 10-3 to less than 10-1,” Dr. Paolino reported. “NGS additionally detected MRD in the range of 10-6 to 10-4 for 160 patients who had undetectable disease on FCM at TP1.”

The greater sensitivity of NGS for MRD is consistent with published studies, Dr. Paolino noted.

Dr. Paolino said the prognostic relevance of low MRD levels is being evaluated “and awaits longer followup.” However, presuming that more sensitive assessment of MRD status at baseline or after induction therapy can guide the intensification of treatment to achieve better outcomes, the use of NGS “is feasible.”

Other NGS Efforts

The multicenter study led by Dr. Paolino is not the only effort to establish NGS as a standard of care for risk stratification in pediatric patients, according to Tara Higgins, PharmD, a clinical specialist in pediatric hematology, oncology and bone marrow transplant at the University of Florida Shands Children’s Hospital, in Gainesville. She said a multicenter study of NGS in the evaluation of pediatric ALL is also being run through the Children’s Oncology Group.

“This multicenter trial and the DFCI study will hopefully be able to determine the best place in practice to utilize NGS as a standard of care,” she told Pharmacy Practice News. “This technology gives providers and pharmacists enhanced information to give more individualized care to these pediatric ALL patients.”

‘This technology gives providers and pharmacists enhanced information to give more individualized care to these pediatric ALL patients.’

—Tara Higgins, PharmD

Drs. Higgins and Paolino reported no relevant fi nancial disclosures. Two co-investigators reported fi nancial relationships with Adaptive Biotechnologies, Jazz Pharmaceuticals, Servier, Syndax and Takeda.

For more news on next-generation sequencing, see page 20.

BiTE Therapy Shows Promise in R/R ALL

By Ted Bosworth

Although only a phase 1b dose-finding study in patients with relapsed/ refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL), all but one patient treated with a subcutaneous formulation of the bispecific T-cell engager (BiTE) blinatumomab (Blincyto, Amgen) achieved a complete hematologic response, with no minimal residual disease (MRD), according to interim data presented at the 2021 annual meeting of the American Society of Hematology.

“The study demonstrated encouraging anti-leukemia activity in a heavily pretreated population,” reported Pilar Martínez Sánchez, MD, PhD, a researcher in the Department of Hematology, Hospital Universitario 12 de Octubre, in Madrid. She called the safety profile “manageable.” Blinatumomab has been available for the treatment of R/R B-cell precursor ALL in adults and children since 2014, but the approved formulation is administered intravenously. In this analysis, six patients received a lower first dose of subcutaneous blinatumomab for several days, followed by a higher subcutaneous dose multiple times weekly. The subcutaneous dose resulted in therapeutic exposures that were comparable to the IV formulation, “with mean average concentrations of 853 mg/mL,” Dr. Sánchez reported.

Within two cycles of blinatumomab treatment, three patients had a complete hematologic response with no measurable MRD. A third patient had achieved a morphological partial response when treatment was discontinued on day 15 of the first cycle after progression of extramedullary disease. Two patients are still on treatment. Both have also achieved a complete response with no MRD.

These results are impressive in a patient population with advanced disease, Dr. Sánchez noted. The median bone marrow blast count was 85%, with only one patient having a blast count greater than 50%. The patients had received up to four prior lines of therapy, and two had relapsed after hematopoietic cell transplantation.

The safety profile was similar to that reported for IV blinatumomab. There were no cases of grade 3 or higher cytokine release syndrome. The data have encouraged further development of an injectable blinatumomab formulation.

“Subcutaneous delivery may improve the convenience and satisfaction of candidates for blinatumomab therapy,” said Dr. Sánchez, indicating that this could expand the routine use of this option in advanced disease.

Taking a Bigger BiTE

These data have the potential to substantially expand the use of this BiTE therapy in ALL and other diseases in which it is active, according to Anthony J. Perissinotti, PharmD, a clinical pharmacist specialist for the Inpatient Hematology Clinical Team at the University of Michigan, in Ann Arbor.

“A major limitation to the widespread use of blinatumomab for R/R ALL or persistent MRD-positive disease is the logistical barrier of a continuous infusion over 28 days for multiple potential cycles,” Dr. Perissionitti said. “A strategy to reduce patient and healthcare resource burden such as subcutaneous administration would be a very welcomed approach clinically and especially for patients and their families.”

Driving CAR T-Cell Rx

continued from page 1

therapy, including patient preference, shorter hospital lengths of stay and freeing up hospital beds for other interventions, Dr. McGann told Pharmacy Practice News in advance of a presentation at the 2022 annual meeting of the Hematology/ Oncology Pharmacy Association. Clinicians also are honing their ability to manage adverse reactions to outpatient CAR T-cell therapy, she said.

In view of those benefits, MUSC was an early adopter of moving the treatments to the outpatient setting, Dr. McGann said. “While there are certain products that we always give on an inpatient basis, we often try to at least give the cells on an outpatient basis to help, as noted, with reimbursement. We may still admit the patients later that night, but at least they receive the cells as an outpatient.”

Indeed, 80% of patients at MUSC are administered the CAR T-cell infusion outside of the hospital, Dr. McGann noted.

Second-Line Therapy

There is yet another driver for moving CAR T-cell treatments beyond the hospital: Several recent studies have indicated the potential benefit of the regimens in second-line therapy, which could dramatically increase the number of patients eligible to receive them. (For a list of the five approved CAR T-cell therapies, see box.) For example, the FDA is expected to act by April 1, on Kite Pharma’s supplemental biologics license application for the use of axicabtagene ciloleucel (Yescarta) as a second-line therapy in relapsed or refractory large B-cell lymphoma (LBCL). In December 2021, findings presented at the American Society of Hematology Meeting & Exposition showed that axicabtagene ciloleucel quadrupled event-free survival (EFS) compared with the current standard of care, which includes high-dose therapy and autologous stem cell transplant (ASCT) (N Engl J Med 2022;386[7]:640-654). At

the same meeting, an interim analysis from the TRANSFORM trial, comparing lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb/Juno) and standard of care, found the CAR T-cell therapy yielded a risk reduction of 65% in EFS in patients with LBCL in the second-line setting (Blood 2021;138[suppl 1]:91).

Those clinical successes come with potentially serious adverse reactions, Dr. McGann stressed, including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome. “But as toxicity management for these therapies has evolved, with early intervention and additional experience resulting in lower rates of acute high-grade toxicity, there have been more opportunities for initial outpatient administration and admission to the inpatient setting only when indicated.”

Still, challenges remain, Dr. McGann stressed, including a “heavy reliance on the patient’s caregiver and daily visits to the treatment center, and you may need immediate inpatient bed availability.” Overall, “you do not have the same ease of close monitoring and interventions that you have with inpatients.”

Creating a set of standard operating procedures can help clinicians navigate at least some of these challenges. Dr. McGann cited three key areas: institutional considerations, product considerations and patient considerations.

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5 Approved CAR T-Cell Treatments

1. Tisagenleleucel (Kymriah, Novartis): relapsed/refractory (R/R) acute lymphocytic leukemia, (ALL), large B-cell lymphoma (LBCL) 2. Axicabtagene ciloleucel (Yescarta, Kite Pharma): R/R LBCL, follicular lymphoma 3. Brexucabtagene autoleucel (Tecartus, Kite Pharma): R/R mantle cell lymphoma, R/R ALL 4. Lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb/Juno): R/R LBCL 5. Idecabtagene vicleucel (Abecma, Bristol Myers Squibb/Celgene): R/R multiple myeloma

certified and enrolled in the Risk Evaluation and Mitigation Strategies (REMS) program, with all relevant staff completing REMS knowledge assessment. Training logs must be maintained, and the institution must comply with audits and report adverse events.

Care coordination. A well-coordinated multidisciplinary team must include a medical director, attending physicians, advanced practice providers, nursing, pharmacy, social work, behavioral medicine, apheresis, cell-processing laboratory and information technology. The emer-

gency department, neuro-oncology, and ICU also must be part of this team.

Appropriate outpatient support. This component includes an outpatient clinic/ infusion center that is open daily, ideally with telemedicine capability, and a CAR T-cell therapy team that is on-call 24/7.

Communication and transitions

of care. These key elements include clearly defined indications for admission, reserved bed availability, and a staff email or “oncology road map.”

“It’s critical that you have support on the outpatient side for having the patient come in every single day, that the whole team is aware of these patients, and that the CAR T–specific on-call service is available at all times,” Dr. McGann said.

Product Considerations

Clinicians should have a strong understanding of the differences in toxicities of each CAR T-cell therapy, Dr. McGann stressed. “For example, Yescarta and Tecartus [brexucabtagene autoleucel, Kite Pharma] have a CD28 costimulatory domain that amplifies early CAR T-cell expansion, which may lead to more toxicities such as CRS. With these agents, we typically lymphodeplete and infuse the cells in the outpatient setting, but then admit the patient in the evening because we anticipate they will develop a fever, which is the first sign of CRS.”

Patient Factors

The patient’s own characteristics are key. “We need to look at things like disease burden. Are patients more at risk of having early-onset and high-grade CRS based on their disease status? What are their comorbidities that may put them at risk for having more severe toxicities? Other concerns include health literacy and compliance. Are patients able to come into the clinic every day? Are we confident that they can take their medications on time and that they can identify early toxicities that may develop at home? Do they have a reliable caregiver who can be there 24/7 to help with the whole process? That’s a vital aspect to giving this therapy in the outpatient setting.”

‘With [axicabtagene ciloleucel and brexucabtagene autoleucel], we typically lymphodeplete and infuse the cells in the outpatient setting, but then admit the patient in the evening because we anticipate they will develop a fever, which is the first sign of [cytokine release syndrome].’ —Mary McGann, PharmD

What Do the Data Say?

It’s also important to follow the data. Dr. McGann cited two recent single-center studies that were reasonably successful in administering axicabtagene ciloleucel and tisagenleleucel (Kymriah, Novartis) in the outpatient setting. In a study from Mayo Clinic, presented at the 2021 annual meeting of the American Society for Clinical Oncology, 64 of 72 axicabtagene ciloleucel

see CAR-T ROLLOUT, page 20

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Combating Resistance to Targeted Therapies

By Gina Shaw

Next-generation sequencing (NGS) has been a useful tool for guiding first-line tyrosine kinase inhibitor (TKI) therapy in patients with non-small cell lung cancer (NSCLC) and other challenging malignancies. Now, clinicians hope that the test also may guide second-line use of these agents.

Given how common it is for tumor cells to mutate and develop resistance to chemotherapy, having NGS on hand to help choose alternative therapies in such cases would be an advantage, noted Chris Kapolas, PharmD, a clinical pharmacy specialist in hematology/oncology at the Kellogg Cancer Center of NorthShore University Health System, in Chicago.

“The availability of drugs to target driver mutations has increased tumor response rates and survival. However, cancer cells continue to mutate beyond the driver mutation, yielding resistance mechanisms to our targeted therapies,” Dr. Kapolas told Pharmacy Practice News in advance of a presentation on the topic at the 2022 annual meeting of the Hematology/Oncology Pharmacy Association, in Boston. “At present, we use NGS to help determine our initial therapeutic approach for targeted therapy, but can we continue to use precision medicine to provide subsequent targeted therapies to patients with resistance mechanisms?” There are several common resistance pathways for various tumor types. “For example, with NSCLC, we initially had the first-generation epidermal growth factor receptor [EGFR] TKIs, such as gefitinib [Iressa, AstraZeneca] and erlotinib [Tarceva, Genetech], and then the secondgeneration agents, afatinib [Gilotrif, Boehringer Ingelheim] and dacomitinib [Vizimpro, Pfizer],” Dr. Kapolas said. “But most patients treated with these first- and second-generation agents develop resistance, with the most common being the EGFRT790M mutation in exon 20.” In November 2015, the FDA approved osimertinib (Tagrisso, AstraZeneca) for the treatment of metastatic NSCLC in patients with T790M mutation-positive NSCLC who had progressed after initial EGFR TKI therapy. In April 2018, that approval was expanded to include

SMOFLIPID (lipid injectable emulsion), for intravenous use BRIEF SUMMARY OF PRESCRIBING INFORMATION

This brief summary does not include all the information needed to use SMOFlipid safely and effectively. Please see full prescribing information, including Boxed Warning for SMOFlipid (lipid injectable emulsion), for intravenous use at www. FreseniusKabiNutrition.com.

WARNING: DEATH IN PRETERM INFANTS • Deaths in preterm infants after infusion of intravenous lipid emulsions have been reported in the medical literature. • Autopsy findings included intravascular fat accumulation in the lungs. • Preterm infants and low-birth-weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion.

INDICATIONS AND USAGE

SMOFlipid is indicated in adults as a source of calories and essential fatty acids for parenteral nutrition (PN) when oral or enteral nutrition is not possible, insufficient, or contraindicated.

Limitations of Use The omega-6: omega-3 fatty acid ratio and Medium Chain Triglycerides in SMOFlipid have not been shown to improve clinical outcomes compared to other intravenous lipid emulsions.

DOSAGE AND ADMINISTRATION

The recommended daily dosage in adults is 1 to 2 grams/kg per day and should not exceed 2.5 grams/kg per day. SMOFlipid 1000 mL is supplied as a Pharmacy Bulk Package for admixing only and is not for direct infusion. Prior to administration, transfer to a separate PN container. Protect the admixed PN solution from light.

CONTRAINDICATIONS

Known hypersensitivity to fish, egg, soybean, or peanut protein, or to any of the active ingredients or excipients. Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides > 1,000 mg/dL.

WARNINGS AND PRECAUTIONS

• Death in Preterm Infants: (see BLACK BOX WARNING) • Hypersensitivity Reactions: SMOFlipid contains soybean oil, fish oil, and egg phospholipids, which may cause hypersensitivity reactions. Cross reactions have been observed between soybean and peanut oil. Signs or symptoms of a hypersensitivity reaction may include: tachypnea, dyspnea, hypoxia, bronchospasm, tachycardia, hypotension, cyanosis, vomiting, nausea, headache, sweating, dizziness, altered mentation, flushing, rash, urticaria, erythema, pyrexia, or chills. If a hypersensitivity reaction occurs, stop infusion of SMOFlipid immediately and undertake appropriate treatment and supportive measures. • Risk of Catheter-Related Infections: Lipid emulsions, such as SMOFlipid, can support microbial growth and is an independent risk factor for the development of catheterrelated bloodstream infections. The risk of infection is increased in patients with malnutrition-associated immunosuppression, long-term use and poor maintenance of intravenous catheters, or immunosuppressive effects of other concomitant conditions or drugs. • Fat Overload Syndrome: This is a rare condition that has been reported with intravenous lipid emulsions. A reduced or limited ability to metabolize lipids accompanied by prolonged plasma clearance may result in a syndrome characterized by a sudden deterioration in the patient’s condition including fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, fatty liver infiltration (hepatomegaly), deteriorating liver function, and central nervous system manifestations (e.g., coma). • Refeeding Syndrome: Reintroducing calories and protein to severely undernourished patients with PN may result in the refeeding syndrome, characterized by the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop. • Aluminum Toxicity: SMOFlipid contains no more than 25 mcg/L of aluminum. During prolonged PN administration in patients with renal impairment, the aluminum levels in the patient may reach toxic levels. Preterm infants are at greater risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Patients with renal impairment, including preterm infants, who receive parenteral intakes of aluminum at greater than 4 to 5 mcg/kg/ day can accumulate aluminum to levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration of

PN products. • Risk of Parenteral Nutrition-Associated Liver Disease (PNALD): PNALD has been reported in patients who receive PN for extended periods of time, especially preterm infants, and can present as cholestasis or steatohepatitis. The exact etiology is unknown and is likely multifactorial. Intravenously administered phytosterols (plant sterols) contained in plant-derived lipid formulations have been associated with development of PNALD, although a causal relationship has not been established. If

SMOFlipid-treated patients develop liver test abnormalities, consider discontinuation or dose reduction. • Hypertriglyceridemia: Impaired lipid metabolism with hypertriglyceridemia may occur in conditions such as inherited lipid disorders, obesity, diabetes mellitus, and metabolic syndrome. • Monitoring/Laboratory Tests: Routinely monitor serum triglycerides, fluid and electrolyte status, blood glucose, liver and kidney function, blood count including platelets, and coagulation parameters throughout treatment. Monitoring patients for signs and symptoms of essential fatty acid deficiency (EFAD) is recommended. • Interference with Laboratory Tests: Content of vitamin K may counteract anticoagulant activity. The lipids contained in this emulsion may interfere with some laboratory blood tests (e.g., hemoglobin, lactate dehydrogenase [LDH], bilirubin, and oxygen saturation) if blood is sampled before lipids have cleared from the bloodstream.

ADVERSE REACTIONS

Most common adverse drug reactions >1% of patients who received SMOFlipid from clinical trials were nausea, vomiting, hyperglycemia, flatulence, pyrexia, abdominal pain, increased blood triglycerides, hypertension, sepsis, dyspepsia, urinary tract infection, anemia and device-related infection. Less common adverse reactions in 1% of patients who received SMOFlipid were dyspnea, leukocytosis, diarrhea, pneumonia, cholestasis, dysgeusia, increased blood alkaline phosphatase, increased gamma-glutamyltransferase, increased C-reactive protein, tachycardia, liver function test abnormalities, headache, pruritis, dizziness, rash and thrombophlebitis. The following adverse reactions have been identified during post-approval use of SMOFlipid in countries where it is registered. Infections and Infestations: infection. Respiratory, Thoracic and Mediastinal Disorders: dyspnea.

To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176, option 5, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS

Coumarin and Coumarin Derivatives, Including Warfarin: Anticoagulant activity may be counteracted; monitor laboratory parameters.

USE IN SPECIFIC POPULATIONS

• Pregnancy and Lactation: There are no available data on risks associated with

SMOFlipid when used in pregnant or lactating women. • Pediatric Use: The safety and effectiveness of SMOFlipid have not been established in pediatric patients. • Hepatic Impairment: Parenteral nutrition should be used with caution in patients with hepatic impairment. Hepatobiliary disorders are known to develop in some patients without preexisting liver disease who receive PN, including cholestasis, hepatic steatosis, fibrosis and cirrhosis (PN associated liver disease), possibly leading to hepatic failure.

OVERDOSAGE

In the event of an overdose, fat overload syndrome may occur. Stop the SMOFlipid infusion until triglyceride levels have normalized. The effects are usually reversible by stopping the lipid infusion. If medically appropriate, further intervention may be indicated. Lipids are not dialyzable from serum.

CAR-T ROLLOUT

continued from page 19 patients (89%) received their cells as outpatients and 8% remained outpatient for the entire month, with a median time to admission of two days (range, 0-25 days) (J Clin Oncol 2021;39[15 suppl]:7554-7554). A University of Pennsylvania study found that 28 of 30 tisagenleleucel patients (93%) received cells on an outpatient basis, with 32% requiring admission and a median time to admission of five days (range, one to seven days) (Blood 2019;134[suppl 1]:3240).

Dr. McGann said her own experiences dovetail with some of the successes seen in these two trials. “Although many of our CAR T-cell patients eventually are admitted,” she said, “by keeping them outpatient until signs of toxicity or other indications develop, we are able to decrease length of stay, decrease costs and increase patient satisfaction.”

first-line treatment of NSCLC exon 19 deletions or exon 21 L858R mutations, based on the results of the phase 3 FLAURA trial, which showed the superiority of osimertinib over first-generation EGFR TKIs as a first-line treatment (Front Oncol 2020;10:602762).

“Chronic myelogenous leukemia [CML] is another example of missense mutations acquired during active therapy,” noted Dr. Kapolas, referring to a type of mutation that occurs due to a DNA error that results in the wrong amino acid being incorporated into a protein. “We will typically start CML patients on imatinib [Gleevec, Novartis], nilotinib [Tasigna, Novartis], bosutinib [Bosulif, Pfizer] or dasatinib [Sprycel, Bristol Myers Squibb].”

The BCR-ABL1 fusion gene is a strong driver mutation in CML, and BCR-ABL TKIs prevent the BCR-ABL protein from exerting its role in the oncogenic pathway in CML. “Eventually, the BCR-ABL gene may acquire missense mutations. Here, common missense mutations include the V299L mutation and the T3151 mutation; these are typically resistant to many of the BCR-ABL TKIs on the market. We have found that second-generation TKIs have improved our ability to achieve high response rates, with various mutations due to increased binding affinity within the ATP binding pocket, except for the T315I mutation.” T3151 confers resistance to all approved BCR-ABL TKIs, with the exception of ponatinib (Iclusig, Takeda), which has a boxed warning for cardiovascular events and liver toxicity. But in October 2021, the FDA approved asciminib (Scemblix, Novartis), known as a STAMP (specifically targeting the ABL myristoyl pocket) inhibitor, for patients who have CML with the T3151 mutation. “It still targets the BCR-ABL mutation, but at an allosteric site,” Dr. Kapolas said.

New Treatment Strategies Needed

Dr. Kapolas suggested considering new approaches—including the use of NGS testing—when targeting these tyrosine kinase mutations. “Since we have TKIs on the market that target some of the resistance pathways, should we obtain another NGS test upon progression on active treatment to identify any acquired resistance pathway as a potential target?” he asked. “That is done right now, with exceptions. When progression occurs while on a first-generation EGFR TKI in metastatic NSCLC, a liquid biopsy might identify a T790M mutation, and if present, that patient would be switched to osimertinib. But if the patient’s first-line treatment is osimertinib, the T790M mutation isn’t likely to occur. Instead, a different alteration, such as mesenchymal epithelial transition [MET] amplification, may result.”

As an example, he cited the May 2021 approval of amivantamab-vmjw (Rybrevant, Janssen), a bispecific monoclonal antibody directed against EGFR and MET receptors in locally advanced or metastatic NSCLC with exon 20 mutations. Researchers are using different cohorts of CHRYSALIS to combine amivantamab-vmjw with the thirdgeneration TKI lazertinib in patients who have developed resistance to osimertinib. The goal “is to see if we can overcome those resistance mechanisms instead of moving to chemotherapy,” Dr. Kapolas said.

“As NGS is becoming more and more available, the future of treating cancer with actionable mutations lies with using NGS upon progression to identify resistance pathways to target,” he added. “If we can further identify mutations causing resistance and target one or more pathways simultaneously, we may be able to outsmart the trickery of the tumor cells, extending progression-free survival and ultimately overall survival.”

Dr. Kapolas reported no relevant fi nancial disclosures.

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