Marijke Vroomen Durning, RN

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. 

Articles

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

The primary end point was ORR, with progression-free survival (PFS), duration of response (DOR), and overall survival (OS) as secondary end points. The main cohort of 99 patients received continuous erdafitinib dosing beginning at 8 mg once daily. After 2 weeks, the dosage was increased to 9 mg daily in the 41% of patients whose serum phosphate levels (a biomarker of FGFR inhibition) were below 5.5 mg/dL and who had no treatment-related adverse events (TRAEs). Treatment con&shy;tinued until disease progression or unacceptable toxicity. The results showed an ORR of 40%; 3% achieved a complete response (CR), and 37% had a partial response. Median PFS was 5.5 months, and median OS was 13.8 months. Twenty-two of the patients had previously received immunotherapy; their response rate was 59%.

Toxicity from erdafitinib was an issue in the study, with grade 3 or higher TRAEs reported in 46% of patients. AEs were mainly managed with dose adjustments but caused 13% of patients to discontinue treatment.

&ldquo;My perspective on this is that the only other true treatment alternatives we have for bladder cancer management are immune ther&shy;apy or, potentially, chemotherapy,&rdquo; Pal said.

&ldquo;Chemotherapy is no walk in the park. It&rsquo;s chal&shy;lenging for patients, particularly elderly patients. If I were to put targeted therapies on that spec&shy;trum, I would say that targeted therapy is still much easier to tolerate than chemotherapy.&rdquo;

Erdafitinib caused central serous retinopathy in 21% of the patients in the BLC2001 study; 76% of these cases were resolved with dose interruption or reduction or by administering a concomitant medication. The most common AEs were hyperphosphatemia and stomatitis, affecting 77% and 58% of patients, respectively.

When the FDA granted accelerated approval for erdafitinib, it also approved Qiagen's

FGFR RGQ PCR Kit. This laboratory test can identify whether a tumor has

mutations or fusions and thus whether the patient is eligible for treatment with erdafitinib.

&ldquo;This supports the fact that even though we still treat most bladder tumors the same way, there are some tumors with fundamental differ&shy;ences,&rdquo; Siefker-Radtke said. &ldquo;As we learn how to target those differences, we can head toward more of a personalized approach and find the best treatment for the right patient.&rdquo;

The other drug to recently receive accelerated FDA approval, enfortumab vedotin, does not require testing for mutations or other biomark&shy;ers.

&ldquo;You don&rsquo;t have to test for the presence of NECTIN4 [expression] because it&rsquo;s present at such a high rate across the urothelial cancers,&rdquo; Siefker- Radtke said. The approval was based on the EV-201 trial, a global, single-arm, phase II study of patients with locally advanced or metastatic urothelial carcinoma who had already undergone treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. The primary end point was ORR; secondary end points included DOR, PFS, OS, safety, and tolerability. Follow-up ranged from 0.5 to 16.5 months, with a median of 10.2 months. The confirmed ORR was 44%, including 12% CRs (

Patients who had liver metastases and those in other prespecified subgroups showed responses similar to those of the overall cohort. Median DOR was 7.6 months, and patients continued treatment until disease progression or unacceptable toxicity.

The most common any-grade TRAEs were fatigue (50%), any peripheral neuropathy (50%), alopecia (49%), any rash (48%), decreased appetite (44%), dysgeusia (40%), and peripheral sensory neuropathy (40%) (

Siefker- Radtke pointed out that, based on the higher diabetic ketoacidosis rates seen in earlier studies, enfortumab vedotin-ejfv may not be a good option for patients with poorly controlled diabetes. These patients also have a higher risk of neuropathy. As a result, the company that manufactures enfortumab vedotin-ejfv has advised that physicians monitor their patients&rsquo; hemoglobin A1C levels, she said.

Pushing for Better Targets, More Sequencing

Research continues to produce more and better targeted therapies for urothelial cancer. Grivas mentioned several of the FGFR inhibitors being studied in clinical trials: rogaratinib, which is undergoing a phase II/III trial (NCT03410693); pemigatinib (NCT03914794); infigratinib (NCT04197986); vofatamab (NCT02401542, NCT03123055; both terminated); Debio1347 (NCT01948297, NCT03834220); and AZD4547 (NCT02546661).

&ldquo;A phase III, multicenter, double-blind, ran&shy;domized, placebo-controlled study evaluating the efficacy of oral infigratinib as adjuvant treatment following surgery in adult subjects with invasive urothelial carcinoma and sus&shy;ceptible

genetic alterations is opening in several centers,&rdquo; he added [NCT04197986]. &ldquo;I think there is also a single-arm phase II study with pemigatinib in the adjuvant setting in Europe. Other compounds are mainly tested in the metastatic setting, while there is also interest in testing [pemigatinib] in NMIBC.&rdquo;

Some agents are also being evaluated in noninvasive disease because of the high rates of bladder cancer recurrence and progres&shy;sion to muscle-invasive disease. According a 2013 study by Karim Chamie, MD, MSHS, and colleagues nearly three-fourths of patients with high-grade NMIBC experience recur&shy;rence within 10 years of diagnosis. Although 41% of recurrences occur without progression, 33% progress to muscle-invasive disease.

Given the new direction in treating urothe&shy;lial cancer, Siefker-Radtke encouraged physicians to pursue mutation testing for their patients with bladder cancer: &ldquo;With the approval of an FGFR-targeted agent, I would argue that everyone who you think is going to tolerate treatment or tolerate an oral pill like erdafitinib should be tested for the presence of [these] mutations, since the drug can help control their disease.&rdquo; Educating physicians is key, Pal agreed. &ldquo;It&rsquo;s important to promote awareness [about] the importance of gene sequencing and bladder can&shy;cer,&rdquo; he said. &ldquo;We put out a physician statement several years ago from the American Society of Clinical Oncology on gene sequencing and bladder cancer. I we were ahead of the curve in the sense that it&rsquo;s been several years since we began using targeted therapies, but those targeted therapies are having a big impact.&rdquo;

Kiss B, Wyatt AW, Douglas J, et al. Her2 alterations in muscle-invasive bladder cancer: patient selection beyond protein expression for targeted therapy. Sci Rep. 2017;7:42713. doi: 10.1038/srep42713.

Colquhoun AJ, Mellon JK. Epidermal growth factor receptor and bladder cancer. Postgrad Med J. 2002;78(924):584-589. doi: 10.1136/pmj.78.924.584.

Rouanne M, Loriot Y, Lebret T, Soria JC. Novel therapeutic targets in advanced urothelial carcinoma. Crit Rev Oncol Hematol. 2016;98:106-115. doi: 10.1016/j.critrevonc.2015.10.021.

Bukhari N, Al-Shamsi HO, Azam F. Update on the treatment of metastatic urothelial carcinoma. Scientific World Journal. 2018;2018:5682078. doi: 10.1155/2018/5682078.

Sylvester RJ, van der Meijden APM, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urology. 2002;168(5):1964-1970. doi: 10.1097/01. ju.0000034450.80198.1c.

O&rsquo;Regan T, Tatton M, Lyon M, Masters J. The effectiveness of BCG and interferon against non-muscle invasive bladder cancer: a New Zealand perspective. BJU Int. 201:116, supplement 3, 54-60. doi: 10.1111/bju.13211.

FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma. FDA website. bit.ly/2H7XDY3. Updated April 12, 2019. Accessed February 10, 2020.

FDA grants accelerated approval to enfortumab vedotin-ejfv for metastatic urothelial cancer. FDA website. bit.ly/2UEbdtZ. Updated December 19, 2019. Accessed February 10, 2020.

Seattle Genetics and Astellas announce updated results from phase 1b/2 trial of Padcev (enfortumab vedotin-ejfv) in combination with immune therapy pembrolizumab as investigational first-line treatment for advanced bladder cancer [press release]. Bothell, Washington, and Tokyo, Japan: Seattle Genetics, Inc, and Astellas Pharma Inc; February 10, 2020. bit.ly/2HbwhjG. Accessed February 11, 2020.

Loriot Y, Necchi A, Park SE, et al; BLC2001 Study Group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Eng J Med. 2019;381(4):338- 348. doi: 10.1056/NEJMoa1817323.

therascreen FGFR RGQ PCR Kit  P180043. May 10, 2019. FDA website. bit.ly/31FMlDT. Updated May 10, 2019. Accessed February 2, 2019.

Targeting Nectin-4 in bladder cancer. Cancer Discov. 2017;7(8):OF3. doi: 10.1158/2159-8290.CD-NB2017-095.

Rosenberg JE, O&rsquo;Donnell PH, Balar AV, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/ programmed death ligand 1 therapy. J Clin Oncol. 2019;37(29):2592-2600. doi: 10.1200/JCO.19.01140.

Chamie K, Litwin MS, Bassett JC, et al; Urologic Diseases in America Project. Recurrence of high-risk bladder cancer: a population-based analysis. Cancer. 2013;119(17):3219-3227. doi: 10.1002/cncr.28147.

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.

Growth Factors Play Emerging Role in Bladder Cancer

As cancer therapies have evolved and individualized treatments have de-veloped over time, patient-centered care has become more prevalent, and oncology teams must consider it to maximize the chances of positive patient outcomes.

Patient-centered care is defined as care that encourages patients to actively participate in their healthcare decisions. When patients are active participants, they are more likely to be satisfied with their care overall and be more adherent to their therapies. But patient-centered care also comprises an approach that individualizes the needs of the patient.

The field of oncology has never been a stand-alone branch of medicine; medical, surgical, and radiation oncologists frequently work with physicians across specialties for the best possible outcomes for their patients. Approaches to individualized patient-centered care may now involve clinicians addressing issues related to aging, fitness, comorbidities, diet, long-term survivorship, and more, in addition to patients&rsquo; systemic therapy regimens.

The treatment of a concurrent psychiatric illness in patients with cancer, whether previously diagnosed or one that developed during cancer treatment, is not new. One study by Susanne Kuhnt, PhD, and colleagues found that the 12-month prevalence of any mental disorder was around 40%, with lifetime rates >50% among all patients with cancer and conditions including depression, anxiety, and addiction.

Given that newer oncology therapies, including biologics, have turned some cancers into chronic diseases, active treatment can last months, with follow-up treatments potentially lasting for years. This extended survival can bring with it additional psychological or psychiatric stress.

In 2008, the Institute of Medicine issued a policy statement regarding psychiatric and psychological care in its report Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs.

This was followed by an American College of Surgeons Commission on Cancer policy in 2015 that required accredited cancer centers to have a program for identifying distressed patients and, when appropriate, referring them to appropriate care.

These and similar guidelines and statements reinforce the changing landscape of cancer treatment and survivorship.

Guy Maytal, MD, assistant professor of clinical psychiatry and chief of integrated care and psychiatric oncology at NewYork- Presbyterian/Weill Cornell Medical College in New York, New York, recommended that oncologists have an open, honest conversation with their patients to determine how they are currently coping with their disease and their new reality as a patient with cancer. This conversation includes questions such as &ldquo;Whom do you turn to for support?&rdquo; as well as those related to how patients cope with stress, he explained.

&ldquo;Then you have to look at what the patient says and how they may have to make adaptations during treatment. For example, some people cope [with everyday stresses] by exercising, but that may no longer be an option for some patients [during treatment]&hellip;some people cope by drinking,&rdquo; Maytal said. &ldquo;[These strategies are] not viable while they are in treatment for cancer. You have to strategize [with the patient] about how they are going to deal with these challenging times.&rdquo;

Depression screening among patients with cancer is helping to improve care, said Maytal. &ldquo;The challenge with screening for anything is that you need to be able to do something if you have a positive screen. [For instance], you would never do mammograms unless you had a breast cancer program,&rdquo; he noted.

Maytal will be delivering his presentation entitled &ldquo;Meeting the Emotional Needs of Your Patients&rdquo; this afternoon at 4:05.

Approximately 60% of patients with a cancer diagnosis are 65 years or older.

This percentage will climb as individuals live longer, both before diagnosis and subsequently with chronic disease. But as patients age, physical and mental problems may also increase. Oncologists are faced with not only comorbidities but also the possibility of decreased physical and mental function among their patients.

Beatriz Korc-Grodzicki, MD, PhD, chief of Geriatrics Service at Memorial Sloan Kettering Cancer Center and professor of clinical medicine at Weill Cornell Medical College, both in New York, New York, said in an interview that when physicians are caring for patients in their 70s, 80s, or 90s, they must keep in mind factors affected by age. &ldquo;[Patients] have different levels of function,&rdquo; she explained. &ldquo;They have different levels of frailty, which need to be taken into account when you are proposing treatment.&rdquo;

Additionally, the disease itself may be affected by age in these patients. &ldquo;Some [tumors] become more aggressive [because of] a prevalence of unfavorable genomic changes or resistance to chemotherapy,&rdquo; Korc-Grodzicki wrote in an article.6 &ldquo;Others, like breast cancer, become more indolent [because of] an increased prevalence of hormone receptorrich tumors and endocrine senescence.&rdquo; And cancer treatment can exacerbate preexisting medical problems as well as cognitive frailty.

According to Korc-Grodzicki, questions that oncologists must consider include:

&bull; Does the patient&rsquo;s level of cognition allow consent to treatment?

&bull; Is the patient able to understand and participate in the treatment?

&bull; Does the patient want to be treated or prefer to live out their life with sup-portive treatment?

&bull; Is the patient fit, frail, or somewhere in the middle?

&bull; Can the patient get to and from appointments, and does the patient have support at home for managing meals, chores, and adverse events (AEs)?

As with patients with existing psychiatric conditions, adherence to treatment can be difficult for seniors who do not have the necessary support. The oncology team needs to be aware of this situation, said Korc-Grodzicki. Seniors who cannot get to the clinic on their own or care for themselves after treatments will not be able to attend regular appointments. This leads to a failure of treatment no matter how effective systemic therapies or treating physicians are, she added.

The National Comprehensive Cancer Network and the International Society of Geriatric Oncology both recommend a geriatric assessment for older patients before starting treatment (TABLE).

Marijke Vroomen Durning, RN | Authors

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