Marijke Vroomen Durning, RN

The pandemic brought about by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has put some aspects of life on hold for over a year now. However, for people living with serious and potentially fatal illnesses, putting life on hold is not an option.

We’re dealing with life and death situations,” said Mark K. Kyei, MD, a medical oncologist at Cleveland Clinic in Ohio, during an interview with 

. “We still need to deliver care for patients and we can’t just compromise because of the pandemic.”

As physicians across all specialties scrambled to find ways to deliver care, oncologists had to balance keeping patients safe from infection with delivering care that frequently has toxic treatments.

“As an infectious disease physician, my team and I were constantly learning, adapting, and implementing protocols based on new science and new evidence—basically everything,” Monika Shah, MD, an infectious disease specialist at Memorial Sloan Kettering Cancer Center in New York, New York, said in an email. “We were in constant motion, especially when there was much uncertainty and real fear, not only from our patients but also our work force.”

Continuing Care Through Virtual and Telehealth Appointments

One could argue that some form of telehealth has existed since patients could speak with their doctor by phone, but systems that deliver effective and consistent care by phone or video are only decades old.

According to a report published by the World Health Organization (WHO) in 2010, “Some predict that telemedicine will profoundly transform the delivery of health services in the industrialized world by migrating health care delivery away from hospitals and clinics into homes.”

But despite its convenience, telemedicine did not become as popular as many people had hoped—until now. Not only did patients and physicians begin to ask for distance visits once they understood the severity of SARS-CoV-2, but the US Congress passed an act in March 2020 allowing providers to bill Medicare for telehealth appointments during the pandemic.

The American Society of Clinical Oncology (ASCO) issued a comprehensive guide to cancer care delivery, updated in December 2020, recommending that clinicians identify patients for whom distance medical appointments would be appropriate, such as those not needing in-person examinations or in-person diagnostics.

“I switched about 50% of my follow-up patients to either telephone visits or video visits,” said Huynh Cao, MD, a medical oncologist at Loma Linda University Health in California. “These were mostly patients who were in remission, though. Patients undergoing treatment that required visits to the clinic could benefit from a hybrid version, however, using phone or video for meetings between active treatments.”

These virtual visits are necessary, but not always ideal. “There’s such a dramatic contrast between in-person and virtual visits,” Kyei said. “I generally prefer to see my patients in the office, talking to them, picking up cues.”

Patients undergoing cancer treatment often need the support of a friend or family member. Oncologists usually encourage patients with a new diagnosis to bring at least 1 person with them for their first visit. But with most facilities banning companions except for hands-on caregivers, this has become particularly challenging for both patient and clinician.

The oncologists at Cleveland Clinic had the policy modified slightly. “In our department, we allowed 1 person, a caregiver or first-degree relative, to accompany [the patient], especially for a new consult,” said Kyei. “Having someone else there, even if that person joins via phone, can help [them] collaborate and corroborate the information, and remember things that we spoke about.”

He also believes that having this extra person is important for patients at follow-up appointments because when they return they often don’t remember what they were told during previous visits. This means that much time is spent reviewing the information.

To address the visitor restrictions at Cancer Treatment Centers of America (CTCA), Ankur Parikh, DO, director of CTCA’s Precision Medicine Program in Philadelphia, Pennsylvania, suggested his patients bring a device to their appointments so they could include a family member or friend through FaceTime or a similar app. And if the patients didn’t have a device, Parikh said that CTCA would help them with a tablet.

“At least they could be part of the conversation and that helps a little bit, although it doesn’t replace having a loved one with you in person.”

Patients must trust their health care teams, particularly while undergoing treatment for a disease such as cancer.

Luckily, I had established relationships with most of my patients [before the pandemic],” said Parikh. This allowed him to have real conversations with his patients, asking about children or work when appropriate, because that connection had been made. But the situation is different with new patients. “To start with a new patient via telemedicine, you don’t get the full story,” he explained. “What you get are screenshots. You don’t always see the patient as you would [in the office].”

In addition, not all patients can participate in virtual visits.4 They may not have a private area to maintain their confidentiality, or they may not have devices or a reliable service for a good connection. This is particularly concerning in certain populations, such as those who are not financially stable or are home insecure.

In April last year, the CMS issued recommendations regarding treatment priorities for low-, intermediate-, and high-acuity treatments or services.5 However, according to news reports, procedures were still being canceled, including surgeries to remove tumors or more definitive testing.6 Although these are not elective procedures, they were considered nonurgent.

Kyei explained that Cleveland Clinic has a 30-day time-to-treat policy, which they are working on maintaining, but the pandemic has caused some variability. “There were instances where initiating treatment took more time,” he said, “especially for patients who required additional procedures before starting treatment, as nonurgent procedures were temporarily suspended.”

Parikh’s experience was different, as scheduled surgeries at CTCA continued for the most part. “We ended up seeing a lot of patients from outside that probably wouldn’t have come to us in the beginning because they’d have [had] their potential curative surgery locally,” he explained.

Quarantine and Fear Affect In-Person Visits

The slowdown of cancer care is not wholly the result of facilities cutting back on in-person visits or performing fewer procedures. It can be due to the patients themselves being unwilling or unable to see a doctor in person.

, 46.35% of the centers providing cancer care reported that more than 10% of their patients had missed at least 1 session.

Obviously, patients who developed coronavirus disease 2019 (COVID-19) could not attend their appointments, but there were also those who may have been exposed to someone with symptoms and had to wait for test results, explained Parikh. This would mean another 2 weeks before they could come in to the hospital or clinic, adding to the delay in care. And, the more possible exposures, the more delays.

Then there is the issue of seeing patients who received a diagnosis later than they might have done before the pandemic. Those who experience concerning symptoms may decide to wait out of fear of subjecting themselves to infection. “We noticed that people put off screening tests because of the virus,” said Kyei. “When some people had symptoms, they delayed because they wanted to wait until things got better, and things never really got better. They ended up presenting with late symptoms, advanced disease.

“We are trying to find other means and ways to prevent this because COVID-19, the impact, has the potential of basically undoing all the progress [in screening] we’ve been able to [make] in the past,” he added.

Although limited to colon cancer, one possible step to mitigate this concern is to increase the availability and use of the noninvasive fecal immunohistochemical (FIT) test, which looks for occult blood. “But if that test is positive, you will still need a colonoscopy, which brings you back to square one,” Kyei noted.

Now that vaccines for COVID-19 are rolling out across the country, where do people with cancer stand? Most, it seems, do want the vaccine. Almost 80% of Parikh’s patients have discussed the vaccine, he said. “Most of my patients are just waiting to be able to get it.” But when they will get it is the bigger question.

Priority for receiving COVID-19 vaccines is decided at the state level, with each state having its own regulations. “In New York State, anyone with cancer or a history of cancer is now eligible for the vaccine,” said Shah. But this is not the case in all states. “At Memorial Sloan Kettering, we prioritize our patients under the state framework, and are rolling it out in a further stratified fashion among our patients, by age and active treatment status.” That being said, the program is subject to vaccine supply, which varies from week to week, so the staff do not know more than a week ahead of time how many people they can vaccinate.

It is not possible to read about the vaccines without reading about their potential adverse effects. Many people report soreness at the injection site, fever, chills, even muscle aches. These symptoms could also be signs of an infection something people with cancer are warned about. This could result in confusion if patients aren’t sure what is causing these symptoms— the vaccine or the start of an infection.

“I told [my patients that] if their fever is mild, about 100 °F or below, then maybe it’s the vaccine,” Cao said. “But if you have a high persistent fever, above 101°F, then please do call us or get help, or go to the ED [emergency department], because it could be something serious.”

Shah agreed. “The main point to counsel a patient about is that the fever and chills associated with the vaccine should be self-limited. Anything prolonged or anything associated with other symptoms, like cough, shortness of breath, or dizziness, for example, requires prompt investigation. Physicians may also need to consider the timing around when the vaccine was given and where in the therapy cycle a patient may be in their treatment plan. If a patient’s white blood cell count is low and they develop a fever, patients should be counseled on what they should be doing in terms of seeking care.”

Solid Tumors Vs Blood Cancers—Any Differences During the Pandemic?

Cancer care during the pandemic is not all that different between oncologists who treat solid tumors and those who treat hematologic malignancies, except when aggressive cancers come in. “Hematological patients tend to have, sometimes, more aggressive disease…so you really don’t have the luxury of just waiting versus someone who may have stable disease, with colon cancer, for example,” Parikh said.

The American Society of Hematology has issued guidance for some types of cancer, such as acute myeloid leukemia (AML), for which they wrote: “Because newly diagnosed AML is considered treatment-emergent in most cases, intensive induction chemotherapy should still be offered for eligible patients (

Regardless of the type of cancer, decisions must be made on a case-by-case basis, Cao said. “For a patient with CML [chronic myeloid leukemia] on maintenance therapy, and all the numbers look good and the disease has been stable for a long time, then we have a little more wiggle room and we can hold a treatment as long as possible,” he explained. “But for a patient with AML, newly diagnosed AML, and who had COVID, then you have to make that hard decision to go ahead with the induction, because if you wait a week or 2, that patient doesn’t have that week or 2 to wait.”

Shah added that her team learned and knew that the risk of having a more severe and/or prolonged illness with COVID-19 was greater in their patients with hematologic malignancy. Thus, COVID-19 screening prior to new treatment initiation became an early strategy at Memorial Sloan Kettering. “For example, we would not want to [give a] transplant to someone with new COVID-19,” she wrote in an email.

The research side of oncology was also affected by the pandemic, both in the lab and clinically. Cao, who oversees a translational lab that focuses on AML treatments, has experienced delays in getting supplies, including the mice his team needs.

For clinical trials, recruitment became a lot more difficult. Participants did not want the extra travel and additional blood draws and other assessments these studies require, said Parikh.

“In some places, almost all clinical trial activity ceased as difficult decisions were made about balancing patient access to critical cancer clinical trials and exposure to COVID-19,” Mark Reeves, MD, PhD, director of the Loma Linda University (LLU) Health Cancer Center, said in an email. “Here at LLU Cancer Center, we kept our trials open for accrual, and made these trials available to patients, but with tremendous care to minimize the risk of COVID-19 exposure. Trial accrual was less here than prior to COVID- 19, but it was still fairly brisk, and it certainly did not come to a halt as it did in many places.”

The delays in clinical trials may come back to haunt us in the future. “We’re not recruiting to the degree as we did [pre-pandemic],” Parikh said, “so that is really impacting the results we are going to get. But we also have to be a little more creative now to structure various trials in the world we are in today.”

Many believe there will be a spike in the diagnosis of more advanced cancers as people finally get screened post pandemic but, according to Kyei, there is another post-pandemic concern: treating patients for cancer years after they have had COVID-19. Although the exact numbers are unknown, many people develop post-infection complications, which could become a pre-existing condition that affects cancer treatment down the road.

“Some people will develop permanent lung damage and cardiac injuries, and neurologic symptoms,” Kyei said. These are issues related to some cancer treatments, although usually among older patients. But with younger patients recovering from COVID-19, the issues could affect treatment options in the future.


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Telemedicine: Opportunities and Developments in Member States: Report on the Second Global Survey on eHealth 2009

. WHO; 2010:10. Accessed March 4, 2021. https://bit.ly/3rtd6q9

2. Coronavirus Preparedness and Response Supplemental Appropriations Act, 2020. Department of Health and Human Services. March 6, 2020. Accessed March 4, 2021. https://bit.ly/3m2wIQP

3. ASCO Special Report: A Guide to Cancer Care Delivery During the COVID-19 Pandemic. ASCO. Updated December 15, 2020. Accessed March 4, 2021. https://bit.ly/3rGr2NX

4. Broom A, Kenny K, Page A, et al. The paradoxical effects of COVID-19 on cancer care: current context and otential lasting impacts. 

. 2020;26(22):5809-5813. doi:10.1158/1078-0432.CCR-20-2989

5. Non-emergent, elective medical services, and treatment recommendations. CMS. April 7, 2020. Accessed March 4, 2021. https://go.cms.gov/39mXbn2

6. Stone W. As coronavirus strains hospitals, cancer patients face treatment delays, uncertainty. NPR. April 2, 2020. Accessed March 4, 2021. https://n. pr/3ryUs04

7. Jazieh AR, Akbulut H, Curigliano G, et al; International Research Network on COVID-19 Impact on Cancer Care. Impact of the COVID-19 pandemic on cancer care: a global collaborative study. 

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8. COVID-19 and acute myeloid leukemia: frequently asked questions. American Society of Hematology. Updated January 22, 2021. Accessed March 4, 2021. https://bit.ly/3u7BEXp

Articles

The pandemic brought about by severe acute respiratory syndrome coronavirus 2 has put some aspects of life on hold for over a year now. However, for people living with serious and potentially fatal illnesses, putting life on hold is not an option.

Lessons Learned From COVID-19— 1 Year Later

A tumor-agnostic approach in which treatment is developed based on a tumor’s genetic and molecular features without regard to the cancer type or primary tumor location in the body, is the focus of the National Cancer Institute (NCI)-MATCH trial (NCT02465060). Investigators from the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) Cancer Research Group and NCI

 sought to determine whether therapy could be better targeted if oncologists could identify molecular alterations using next-generation sequencing (NGS) and administer currently available approved or experimental drugs—either singly or in combination—tailored to those targets. Results of this umbrella/basket trial were published in the November 2020 issue of the Journal of Clinical Oncology.

“The objective of this study was to determine whether matching drugs targeted against a specific gene abnormality would be effective in treating patients [with cancer] with that mutation, regardless of their tumor type,” said Lyndsay Harris, MD, in an email interview with Targeted Therapies in Oncology. Harris is the associate director of the Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis at NCI in Bethesda, Maryland, and one of the study report’s coauthors.

The MATCH trial comprised 30 parallel, single-arm, phase 2 subprotocols. Each subprotocol, or arm, featured a different molecular marker-treatment pair. Patients with tumor alterations that could be addressed by a targeted treatment were assigned to the corresponding arm, irrespective of tumor histology. For example, subprotocol H (EAY131-H) investigated the selective BRAF inhibitor dabrafenib (Taflinar) and the MEK1/2 inhibitor trametinib (Mekinist) in patients with BRAF V600–mutant cancers.

A database that catalogs mutations associated with different tumor types already exists. However, this database, The Cancer Genome Atlas, concentrates on primary tumors that could potentially respond to surgery, either alone or as part of a broader treatment regimen. MATCH, on the other hand, enrolls patients who have relapsed/refractory advanced or metastatic disease.

Nearly 6000 adults have enrolled in the multiarm trial. Eligible patients could have any solid tumor, lymphoma, or myeloma that either had progressed despite standard therapy or for which no curative treatment was available. Other inclusion criteria were an ECOG performance status of 1 or better and adequate hematopoietic, kidney, and liver function.

Patients were required to submit a tumor biopsy specimen obtained within 6 months of study registration. A total of 5540 biopsy samples were sequenced.

Of the 5540 patients screened, 38% had tumors that harbored actionable mutations and 18% were assigned to treatment arms. Of the assigned patients, 70% (n = 686) were ultimately enrolled in a subprotocol arm and received treatment. The accrual goal for each subprotocol was at least 31 eligible patients; as of November 2020, 11 subprotocols had reached this goal.

 Currently, 11 trial arms are open and recruiting patients (TABLE).

There were 4 major findings from the study:

The proportion of patients who had gene abnormalities that matched targeted drugs was 37.6%.

Uncommon cancers had some of the highest match rates.

Many patients’ tumors had more than 1 genetic driver of cancer growth.

Genetic defects exhibited surprisingly little change between primary and metastatic tumors.

It's noteworthy that the trial established the feasibility of sequencing large numbers of tumors in a short time frame. The speedy return of results will enable targets to be identified in time for therapy decisions, according to Harris.

Most Frequent Mutations Not Necessarily Actionable

The most frequently found mutations were in 

 (47.4%), KRAS (21.2%), and APC (12.4%). Among co-occurring mutations, the pair with the highest incidence was 

 Despite their frequency, some of the most commonly observed mutations were not actionable; when MATCH was initiated, there were few drugs targeting cancers with 

 mutations, for example. As a result, there was no subprotocol for this patient segment.

For many common molecular subsets, though much is known, there remains the need to develop actionable therapies.

 (6.3%) were the most common. All other actionable mutations occurred in 3% or fewer of patients.

Although targeted therapies were not currently available for many of the patients’ tumors, this study does have important implications for targeted therapy approaches. MATCH demonstrated that genomic sequencing will reveal targets of interest in a substantial proportion of patients, Harris pointed out, adding, “As we move into an era of more extensive sequencing, it is certain that additional targets will be discovered.” Additionally, Harris noted that a large number of mutations that could lead to treatment resistance was identified in many tumor types, which may explain why some of the study arms had lower response rates.

“We know that melanoma has a high percentage of patients with 

 mutations,” said April K.S. Salama, MD, a medical oncologist at Duke Cancer Center in Durham, North Carolina, and an investigator on subprotocol H, during an interview with Targeted Therapies in Oncology.

Targeted therapies have led to significant improvements in patient survival and outcomes, and they have been shown to be effective therapies for melanoma.

“While we’ve seen these great response rates in melanoma and some other cancers, like thyroid cancer, we’ve seen relative resistance in cancers like colorectal cancer that, despite having 

 mutations and despite getting these highly selective BRAF and MEK inhibitors, showed relatively little benefit and pretty low response rates. And [the inhibitors were] felt not to be all that effective,” Salama said. “And that’s where a trial like MATCH and others like it come in.”

According to Salama, these types of studies can flip the traditional cancer trial, for which a patient must have a certain cancer type to enroll. Instead, MATCH enrolled patients based on certain molecular features. Although there was uncertainty about whether this one-size-fits-all approach would be feasible with 

 mutations and whether the same drugs would be efficacious in different cancers, her subprotocol study produced positive findings. “It provided further data to suggest that inhibiting BRAF may be an effective strategy against the majority of 

-mutated cancers.” Salama acknowledged that her study included only approximately 30 patients, and pointed to interest in expanding the research.

As noted above, one important finding from MATCH was an average match rate of nearly 38% between genetic alterations and targeted therapies. Rather moderate match rates were found in the most common cancers: non–small cell lung cancer (NSCLC; 17.4%), colorectal cancer (13.7%), breast cancer (17.8%), and prostate cancer (23.0%). Cancers with assignment rates more than 25% included central nervous system cancer (37.2%), urothelial cancer (36.0%), cholangiocarcinoma pancreaticobiliary cancer (25.9%), cervical cancer (28.4), gastroesophageal cancer (27.8%), melanoma (26.3%), uterine cancer (26.2%), and anal cancer (25.5%). The lowest actionability rates were found in pancreatic cancer (5.8%), small cell lung cancer (5.1%), and lymphoma (5.0%).

The second important finding was that some uncommon cancers, such as cholangiocarcinoma, pancreaticobiliary, gastroesophageal, and cervical, had some of the highest match rates. The most common cancers (breast, colorectal, NSCLC, and prostate) had rates that hovered around 17%. “Although the match rate varied widely across the board, some of the less common/rare tumors had the highest match rates, reflecting the larger number of actionable mutations in those types,” Harris said.

Another important point made by the investigators regarded the study’s utility. Using NGS, they wrote, patients could be triaged to investigational therapies, “provided that a sufficiently large pool of agents is made available.”

Although much research still needs to be done, Harris explained that these findings should encourage community oncologists to direct patients to further trials. “Oncologists should understand that tumor sequencing in metastatic populations is likely to lead to discovery of a potentially actionable mutation that could provide further opportunities for treatment for their patients,” she said. “Furthermore, in advanced, often heavily pretreated cancer populations, single-agent targeted therapies may not be adequate and combinations of agents may be necessary.” Patients enrolling in clinical trials of such combinations would help the oncology community further develop optimal therapies, which would potentially provide greater benefit to patients.

Another benefit of MATCH was the accessibility of the trial. Support from the NCI's National Clinical Trials Network and Community Oncology Research Program made the study broadly accessible to local communities. “In fact, the majority of the patients came from community sites,” Harris said. “This demonstrates that clinical trials such as these can allow physicians to treat their patients where they live, rather than needing to travel to an academic site, and should be encouraged. The MATCH trial is ongoing and enrolling patients at more than 1100 cancer centers and community hospitals in every state, the District of Columbia, and Puerto Rico.”

The MATCH trial is just the beginning. “Although we did see a number of study arms that met their primary end point[s] for the study, the majority had lower response rates,” Harris said. “We discovered a large number of resistance mutations in these tumors, suggesting that a single target may not be sufficient for efficacy in a patient with an advanced tumor.” A new study, ComboMATCH, has been launched and will look at combinations of targeted agents. Like the original trial, ComboMATCH will be a signal-seeking study. Although MATCH treatments mostly consist of single drugs, ComboMATCH will test combinations of targeted drugs sup-ported by preclinical in vivo evidence. The principal is to overcome drug resistance to single-agent therapy by developing genomically-directed targeted agent combinations.

 Harris encouraged oncologists to direct patients to clinical trials such as MATCH.

Salama agreed. “We know that many adult patients in oncology are not treated in clinical trials,” she said. “I think continued interest and participation in clinical trials ... is what we really need to advance the field.”

Liu A. Large genomics study points the way to future cancer clinical trials. 

. October 14, 2020. Accessed January 6, 2020. 

Genomic study of 6000 patients in NCI-MATCH precision medicine cancer trial. ECOG-ACRIN. October 13, 2020. Accessed January 6, 2020. 

Flaherty KT, Gray RJ, Chen AP, et al; NCI-MATCH Team. Molecular landscape and actionable alterations in a genomically guided cancer clinical trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH). 

. 2020;38(33):3883-3894. doi:10.1200/JCO.19.03010

Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib in patients with tumors with BRAFV600E mutations: results of the NCI-MATCH trial subprotocol H. 

. 2020;38(33):3895-3904. doi:10.1200/JCO.20.00762

Breindle A. NCI-MATCH data give insights into late-stage tumors. 

. October 16, 2020. Accessed January 6, 2020. 

Flaherty KT, Gray R, Chen A, et al; NCI-MATCH Team. The molecular analysis for therapy choice (NCI-MATCH) trial: lessons for genomic trial design. 

. 2020;112(10):1021-1029. doi:10.1093/jnci/djz245

National Cancer Institute. NCI-MATCH trial (molecular analysis for therapy choice). Accessed January 6, 2021. 

Ray T. NCI-MATCH data shows value of platform trials for patients with rare genomically driven cancers. 

ECOG-ACRIN Cancer Research Group. Precision medicine cancer trial NCI-ComboMATCH/EAY191. July 2, 2020. Accessed January 22, 2021. 

A tumor-agnostic approach in which treatment is developed based on a tumor’s genetic and molecular features without regard to the cancer type or primary tumor location in the body, is the focus of the National Cancer Institute -MATCH trial. 

NCI-MATCH Trial Explores Tumor-Agnostic Approach

Chimeric antigen receptor (CAR) T-cell therapies quickly burst into the spotlight of hematology-oncology disease management because of their potential to illicit deep and durable responses from patients whose disease is relapsed or refractory to multiple previous lines of therapy. Relevant professional meetings and oncology publications exploded with research and news about CAR T cells, and this cellular therapy strategy is now being explored across hematologic and solid malignancies.

“CAR T cells are a scientific revolution,” Tania Jain, MBBS, assistant professor of oncology at Johns Hopkins University in Baltimore, Maryland, said in an interview with 

 (TTO). “They have brought about a paradigm shift in terms of how we’re treating patients.”

The 2 currently FDA-approved CAR T-cell therapies, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah), are both indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma; additionally, tisagenlecleucel is approved for patients up to 25 years with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

With a second wave of approvals likely on the horizon for therapies such as lisocabtagene maraleucel (liso-cel) and idecabtagene vicleucel (bb2121), CAR T is gaining traction and will likely play an increasingly prominent role in the future treatment paradigm in oncology.

CAR T-cell therapy administration is largely limited to the inpatient setting at both academic institutions and large accredited cancer centers, making such treatments unavailable to most patients. Other challenges with this type of therapy include its potential to cause serious toxicities resulting in organ damage and death.

Due to the promising efficacy of these agents, investigators have been working toward viable solutions to bring CAR T-cell therapies to more patients by alleviating difficulties associated with therapy delivery and patient care.

Barriers to Manufacturing CAR T Cells Are Addressed

CAR T-cell therapies, both those currently approved and the many being explored in late-phase clinical trials, are produced from autologous T cells obtained from the patient receiving therapy. This personalization has led to tremendous success, yet it is a large part of why CAR T-cell therapy use remains limited to a select group of patients.

Time is an important consideration for patients who have experienced multiple relapses and may be too weakened by numerous lines of prior therapy to wait several weeks for the CAR T-cell manufacturing process. The effects of previous treatments or the disease itself can also present challenges, as manypatients are rendered lymphopenic and may be unable to produce enough T cells for harvesting. Roadblocks may remain for patients who are not limited by these factors; manufacturing success and effectiveness of the CAR T-cell product can be negatively influenced by disease-related dysfunctions of patients’ T cells.

A new option, off-the-shelf CAR T-cell products, may help solve these problems. These premade products are manufactured using allogeneic donor cells (instead of autologous cells from the patient), and they present immediate advantages to clinicians, such as immediate availability, opportunity for product standardization, and decreased cost.

“The advantages [include] being able to access the cellular therapy in real time, as opposed to autologous products that havetobe manufactured,”Craig S. Sauter, MD, clinical director of the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center in New York, New York, explained in an interview withTTO. This is particularly important for patients who are not responding to therapy, which is a current requirement for treatment with CAR T cells, he added.

Findings from a phase I trial (NCT01430390) in patients with relapsed or refractory B-cell malignancies showed that patients with non-Hodgkin lymphoma (NHL) experienced durable responses with an Epstein-Barr virus–specific cytotoxic lymphocyte CAR product derived from cells harvested from third-party donors (rather than from their more precisely matched stem cell donors). All 4 patients with NHL and a single patient with chronic lymphocytic leukemia, who were treated with third-party cells, remained disease free and alive at the time of analysis, with a median follow-up of over 2 years.

“The advantages [of this type of therapy are] that it eliminates the need for apheresis [and] shipping cellular products back and forth. [Instead, clinicians] have a pharmaceutical product on the shelf for access,” Sauter, who was an author on the trial, said. Another notable product being investigated in clinical trials is UCART19, an allogeneic engineered anti CD19CAR T-cell product, which is being evaluated in the phase I CALM trial in adult patients with relapsed or refractory B-cell ALL (NCT02746952) and in the phase I PALL trial of pediatric patients with relapsed or refractory CD19-positive B-cell ALL (NCT02808442). Other off-the-shelf agents are described in theTABLE.

Optimizing Adverse Event Management for the Outpatient Setting

Issues with inpatient CAR T-cell therapy administrationinclude high demands on health care resources and strain on patients and their families. Moving treatment to the outpatient setting has the potential to reduce this strain; however,clinicians taking over care of patients receiving CAR T-cell therapy must be prepared with the proper resources to identify and manage adverse events associated with therapy.

One of the most notable risks to patients receiving CAR T-cell therapy is cytokine release syndrome (CRS), a systemic inflammatory response that is characterized by increased serum levels of inflammatory cytokines, fever, hypotension, hypoxia, and organ dysfunction.

 “[CAR T] can also lead to neurological events and can cause confusion and, in some patients, seizures,”Carlos R. Bachier, MD, Director of Cellular Research at Sarah Cannon Cancer Center in Nashville, Tennessee, explained in an interview with TTO.

Regardless of the infusion setting, patients require close monitoring in the hours and days following therapy administration. A review byLucrecia Yáñez, PhD, MS, and colleagues stated that key criteria for treating patients in the outpatient setting include an educated caregiver and necessary infrastructure allowing for outpatient visits plus adequate emergency and intensive care unit (ICU) access. Patients followed as outpatients must be given twice-daily temperature checks for a minimum of 14 days following treatment and preferably extending up to 3 to 4 weeks following infusion. Anysigns of back pain, skin rash, dizziness, chills, shortness of breath, chest pain, tachycardia, or neurological events that may indicate neurotoxicity or signs of CRS must be reported immediately so treatment can begin as quickly as possible.

Because of the risk of CRS and neurotoxicity, both FDA-approved agents are restricted under the Risk Evaluation and Mitigation Strategy, an FDA-mandated program that builds in caution for use of agents with serious safety concerns.

 Therefore, 2 doses of tocilizumab (Actemra), an interleukin (IL)-6 receptor antagonistthat was approved in 2017 for management of CRS associated with CAR T-cell therapy,

should be on hand for each patient before the infusion of CAR T cells. Steroids have also demonstrated efficacy against CRS, but concernssurrounding CAR T-cell suppression with these agents have established them as a second-line choice after tociluzumab.

Immune effector cell–associated neurotoxicity syndrome (ICANS) is a group of neurologic symptoms associated with treatments such as CAR T-cell therapy. Predisposing factors include younger age, higher tumor burden, high levels of pretreatment inflammation, and history of early or high-grade CRS. Treatments for complications of ICANS vary. Some centers may prescribe prophylactic antiepileptic medications, such as levetiracetam, to prevent seizures in patients with grade 2 or higher neurologic events. Anti–IL-6 therapy can be considered in patients with concurrent CRS, but corticosteroids are the preferred regimen in those with neurotoxicity alone.

Moving Liso-Cel to the Outpatient Setting

In February of this year, the investigational CAR T-cell product liso-cel was granted priority review by the FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma who had undergone at least 2 prior therapies.

Investigators believe that liso-cel therapy may have a place in a broad range of patients and in the outpatient setting.

“It turns out liso-cel has a low incidence of [CRS and ICANS], and they occurred relatively late compared with other products,” said Bachier. “Because of this low incidence, the strategy was to deliver liso-cel in an outpatient setting.”

The feasibility of liso-cel administration on an outpatient basiswas evaluatedby Bachier and colleagues, and the results were presented at the 2020 Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and Cellular Therapy and the Center for International Blood & Marrow Transplant Research, held February 19 to 23, 2020, in Orlando, Florida.

The authors analyzed data from 3 clinical trials of liso-cel, with a focus on the subset of participants who were treated as outpatients. The included trials were the phase I TRANSCEND-NHL-001 (NCT02631044) and phase II OUTREACH (NCT03744676) trials in patientswhohadundergone at least 2 lines of prior treatment, as well as the PILOT study (NCT03483103), which examined liso-cel as second-line therapy in patients who were ineligible for autologous hematopoietic stem cell transplant because of age, organ function, or ECOG performance score. All 3 studies allowed outpatienttreatment, with some patients receiving their therapy in the nonuniversity setting.

“This clinical trial included sites that were not a part of a university but had experience treating patients for stem cell transplant,” Bachier said. “Some of these sites that participated were notyour traditional university centers that had traditionally been involved in the development of these therapies.”

Much caution was required in order to maximize patient safety and treatment efficacy. “The approach of doing CAR T-cell therapy, in general, in the outpatient setting requires a robust clinical ability of the centers,” said coauthor David G. Maloney, MD, PhD, medical director of Cellular Immunotherapy at the Immunotherapy Integrated Research Center of Fred Hutchinson Cancer Research Center in Seattle, Washington, in an interview. “We were able to get people safely to the hospital, and it was rare that you would have to do escalation of care when people were admitted. Most of the time, patients could bemanaged…and wereout of the ICU, withrare exceptions. But again, you still have to have the wherewithal to get patients to the ICU pot entially for aggressive care if needed.”

Results of the analysis of outpatient data from the 3 trials showed that rates of toxicity and response were similar to those previously reported for the entire patient cohort (both inpatients and outpatients) of the TRANSCEND-NHL-001 trial.

“Based on these results, the indication is that you can deliver [liso-cel] in the outpatient setting and the outcomes are good compared with those treated in the inpatient setting,” said Bachier. “Aside from that, it also showed that liso-cel could be safely administered outside of university programs and in more community-based programs, most of them being aligned [with] or part of stem cell and bone marrow transplant programs.”

Next Steps for Bringing CAR T Into More Clinical Settings

When planning or setting up a CAR T-cell therapy outpatient program, investigators anticipate possible barriers to successfultreatment. The greatest barrier, according to Bachier, is access to physicians and staff who are knowledgeable and trained to manage toxicities related to CAR T-cell therapy. “These therapies still should not, in my opinion, be delivered [by clinicians in] community centers that do not have the expertise to deliver the therapies safely,” he said.

Maloney added that centers should be required to have the ability to triage patients 24/7 and allow for patients to be directly admitted to the hospital if needed. In the case of the analysis of outpatient data from the 3 liso-cel trials however, he said, “We found that around 30% to 40% of patients did not actually ever require hospitalization, whichis quite interesting.” Most of the 60% to 70% of patients who were hospitalized were admitted for fever, he added.

In addition, sites must gain accreditation and approval, Jain pointed out.

“Every center that intends to do CAR T-cell therapy is first approved by each of the companies [that manufacturethese agents],” Jain said. “The centers also have to be approved by FACT [Foundation for the Accreditation of Cellular Therapy], which is the same organization that approves centers for allogeneic stem cell transplant. These are some of the largest things that a center needs to go through, which takes care of things like developing standard practices and other guidelines to make sure that these [therapies] are used safely and appropriately.”

Forward-Looking Aspects of Cellular Therapy

As investigators and oncologists explore the feasibility of moving CAR T-cell therapy into more settings, 2 questions arise: What settings have on this therapy?

What type of training and skills do clinicians need? Like other clinicians, Sauter has concerns about new allogeneic cellular therapies,andhe hopes future research will focus on mitigating these challenges. “The concern would be that these are not autologous products and there is the risk of rejection from the host immune system,” he said. “Strategies to circumnavigate that risk are at the forefront of investigationin off-the-shelf CAR T cells.”

The research is not stopping with CAR T-cell therapy,though. “We’re seeing a lot of new molecules coming in that will be challenging the roles of CAR T cells, [such as] specific antibodies, which may even work in cases of CAR T-cell failure,” Maloney said. “We are still learning how to make those more effective and safer.”

1. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine releasesyndrome.FDAwebsite.PublishedAugust30,2017.AccessedApril14, 2020. bit.ly/2RC4eQ8

2. FDA approves axicabtagene ciloleucel for large B-cell lymphoma. FDA website. Published October 18, 2017. Accessed April 14, 2020. bit.ly/2yYIQOp

3. FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. FDA website. Published May 1, 2018. Accessed April 14, 2020. bit.ly/34zPoi8

4. Rafiq S, Hackett CS, Brentjens RJ. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat Rev Clin Oncol. 2020;17(3):147167. doi: 10.1038/s41571-019-0297-y

5. DepilS,DuchateauP,GruppSA,MuftiG,PoirotL.‘Off-the-shelf’allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov. 2020;19(3):185199. doi: 10.1038/s41573-019-0051-2

6. Curran KJ, Sauter CS, Kernan CS, et al. Durable remission following “off-theshelf” chimeric antigen receptor (CAR) T-cells in patients with relapse/refractory (R/R) B-cell malignancies. Presented at: 2020 Transplantation & Cellular Therapy Meetings; February 19-23, 2020; Orlando, FL. Abstract 120. bit.ly/2ufDYCu

7. Yáñez L, Sánchez-Escamilla M, Perales MA. CAR T cell toxicity: current managementandfuturedirections. Hemasphere.2019;3(2):e186.doi:10.1097/ HS9.0000000000000186

8. Risk evaluation and mitigation strategies | REMS. FDA website. Updated August 8, 2019. Accessed April 14, 2020. bit.ly/2ykhLVt

9. JainT,BarM,KansagraAJ,etal.UseofchimericantigenreceptorTcell therapy in clinical practice for relapsed/refractory aggressive B cell non-Hodgkin lymphoma: an expert panel opinion from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. 2019;25(12):2305-2321. doi: 10.1016/j.bbmt.2019.08.015

10. U.S. Food and Drug Administration (FDA) accepts for Priority Review Bristol-Myers Squibb’s Biologics License Application (BLA) for lisocabtagene maraleucel (liso-cel) for adult patients with relapsed or refractory large B-cell lymphoma. News release. Bristol-Myers Squibb; February 12, 2020. Accessed April 15, 2020. bit.ly/37ruQbs

11. Helwick C. Strong activity shown for lisocabtagene maraleucel CAR T-cell therapy in aggressive large B-cell lymphoma. ASCO Post website. Published February 25, 2020. Accessed April 15, 2020. bit.ly/3eoD0pT

12. Bachier CR, Palomba ML, Abramson JA, et al. Outpatient treatment with lisocabtagene maraleucel (liso-cel) in 3 ongoing clinical studies in relapsed/refractory (R/R) large B cell non-Hodgkin lymphoma (NHL), including second-line transplant noneligible (TNE) patients: TRANSCEND NHL 001, OUTREACH, and PILOT. Presented at: 2020 Transplantation & Cellular Therapy Meetings; February 19-23, Orlando, FL. Abstract 29. bit.ly/37I7DC9

Relevant professional meetings and oncology publications exploded with research and news about chimeric antigen receptor T cells, and this cellular therapy strategy is now being explored across hematologic and solid malignancies.

 Protocol Management, Off-the-Shelf Therapies Help Bring CAR T Into More Settings

were introduced, it had been more than 30 years since any new drugs had been approved for the treatment of urothelial cancer.

Recently, 2 new noncheckpoint inhibitors, erdafitinib (Balversa) and enfortumab vedotin-ejfv (Padcev), reached the market, and more may be available soon.

Despite the benefit immune checkpoint inhibitors (ICIs) have delivered in the advanced setting for frontline cisplatin-ineligible disease, as well as in the platinum-refractory setting, there remains a significant number of patients who do not respond. Looking beyond ICIs, investigators have focused on EGFR, HER2, HER3, and FGFR3 receptors. Erdafitinib (Balversa) and enfortumab vedotin-ejfv (Padcev) are 2 non-ICIs that have gained recent entry into the market, but more are on the way.

Altered growth factors and signaling pathways have been found to be drivers of specific types of bladder cancer, said

, asso&shy;ciate clinical professor in the Department of Medical Oncology and Therapeutics Research and codirec&shy;tor of the kidney cancer program at City of Hope in Duarte, California, during an interview with

) is involved in sig&shy;naling pathways that control how cells grow and divide.

overexpression results in ideal conditions for malignant growth, with increased angiogenesis and decreased apoptosis.2 Potentially actionable alter&shy;ations in genes such as

, and fibroblast growth factor receptor 3 (

) are present in up to 60% of high-grade urothelial cancers.

Patients with muscle-invasive bladder cancer (MIBC) have a relatively high rate of

alterations, with higher rates found only in breast and gastric cancers, who also frequently have

is also an important one,&rdquo; Pal said. &ldquo;It seems to be a driver in about 20% of patients with bladder cancer; at least, that&rsquo;s how often we find that the pro&shy;tein gets mutated.&rdquo;

The challenge: identifying which patients would benefit from treatments that target these growth factor receptors.

&ldquo;In the past, attempts we have had to target these pathways have been unsuccessful, mainly because we have not been able to select the patients properly,&rdquo; explained

, a medical oncol&shy;ogist at Seattle Cancer Care Alliance in Washington, associate professor of oncology at the University of Washington (UW) School of Medicine in Seattle, and clinical director of the genitourinary cancers program at UW Medicine. I think it&rsquo;s a patient selection issue, as well as having the appropriate drugs and biomark&shy;ers,&rdquo; he said during an interview with

is present in approximately 50% of bladder cancer cases. It is also found in these cancer types: nonsmall cell lung (40%-80%), colorec&shy;tal (25%-77%), advanced gastric (33%), pancreatic (30%-50%), ovarian (35%-70%), breast (15%-30%), and prostate (40%).

&ldquo;With lung cancer therapy, investigators are furthest along because they have recognized and targeted multiple altered proteins,&rdquo; Pal said. &ldquo;They are well characterized, so you can triage and allocate therapy on the basis of the specific mutations and genes that result in abnormal proteins. It&rsquo;s different in bladder cancer, where

is the only gene that is mutated [and has] an associated FDA-approved prod&shy;uct at this point.&rdquo;

Grivas agreed with Pal: &ldquo;I do not think that we had successes in targeting

in urothelial can&shy;cer, maybe because of the lack of proper patient selection. Moreover, the frequency and the driving nature [of] those alterations might be different in urothelial cancer.&rdquo;

The primary goal of treatment for non-MIBC (NMIBC) is prevention of progression to MIBC. Standard initial treatment for NMIBC is transurethral resection of blad&shy;der tumor (TURBT), immediately followed by adjuvant intravesical chemotherapy. Depending on the patient&rsquo;s risk level, short-term or ongoing treatment with intra&shy;vesical Bacillus Calmette-Gu&eacute;rin (BCG) may be offered, with radical cystectomy reserved for BCG-ineligible patients or those with the highest risks of recurrence and progression. Systemic chemotherapy with cispla&shy;tin plus gemcitabine or accelerated (dose-dense) MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) has long been the standard first-line treatment for metastatic urothelial carcinoma and is also given to fit patients prior to radical cystectomy. Attempted blad&shy;der preservation with maximum TURBT followed by chemoradiation is used in selected patients. Systemic therapies for advanced disease include platinum-based chemotherapy; immune checkpoint inhibitors, such as pembrolizumab (Keytruda), atezolizumab (Tecentriq), nivolumab (Opdivo), avelumab (Bavencio), and durvalumab (Imfinzi); and the recently approved erdafitinib and enfortumab vedotin-ejfv.

&ldquo;Until now, we were limited in treatment options for bladder cancer,&rdquo; said Arlene O. Siefker-Radtke, MD, a professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston. &ldquo;We had cisplatin-based chemotherapy as the best standard,&rdquo; she told

Recently, oncologists gained new tools for their armamentarium: targeted therapy with erdafitinib or enfortumab vedotin-ejfv. In April 2019, the FDA granted accelerated approval to erdafitinib, a pan- FGFR tyrosine kinase inhibitor, for the treat&shy;ment of locally advanced or metastatic urothelial carcinoma with activating

alterations that has progressed during or after platinum-based chemotherapy.

Enfortumab vedotin-ejfv is an antibody-drug conju&shy;gate that targets NECTIN4, a transmembrane protein expressed in over 80% of bladder cancers. In December 2019, this agent also received accelerated FDA approval for the treatment of patients with locally advanced or metastatic urothelial carci&shy;noma who had already received platinum-based che&shy;motherapy and a PD-1 or PD-L1 immune checkpoint inhibitor.

In EV-103, 45 patients treated with the com&shy;bination of enfortumab vedotin-ejfv and pembrolizum&shy;ab were evaluated for safety and efficacy. After a median follow-up of 11.5 months, the study results continue to meet outcome measures for safety and demonstrate encouraging clinical activity for this plati&shy;num-free combination in the first-line setting. Updated results were presented February 14 during an oral session at the 2020 Genitourinary Cancers Symposium in San Francisco, California.

One of the biggest problems with chemother&shy;apy regimens, however, is the level of toxicity, particularly in patients with bladder cancer, who tend to be older. &ldquo;There was great excitement in the field and great hope with the immune check&shy;point inhibitors,&rdquo; Siefker-Radtke continued. &ldquo;The original trials suggested a 40% objective response rate [ORR]. But with larger studies, we saw the response rate drift down to around 20%. I think that was a sign of the field being desper&shy;ate for new agents and better options, so even a response rate of 20% was a wonderful thing.&rdquo;

The erdafitinib approval was based on data from BLC2001, a multicenter, open-label, phase II study of patients with locally advanced, unre&shy;sectable, or metastatic urothelial carcinoma who had progressed on or after at least 1 prior chemotherapy regimen and had at least 1 of a prespecified list of

When checkpoint inhibitors<strong>&nbsp;</strong>were introduced, it had been more than 30 years since any new drugs had been approved for the treatment of urothelial cancer. Recently, 2 new non&ndash;checkpoint inhibitors, erdafitinib and enfortumab vedotin-ejfv, reached the market, and more may be available soon.

Marijke Vroomen Durning, RN | Authors

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Protocol Management, Off-the-Shelf Therapies Help Bring CAR T Into More Settings

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