INTRODUCTION

Oncology care in the 21st century is no longer built around the traditional treatments of cytotoxic chemotherapy, surgery, and radiation. While these strategies may offer curative options in some patients, clinical outcomes are variable, toxicities of these nonspecific cytotoxic therapies sometimes can have acute and chronic effects on patients, and responses and tolerance to treatment differ greatly because of the heterogeneity of different malignancies.¹

Today, targeted therapies are individualized for patients and their disease. Expanding knowledge of cancer biology has led to identification of tumor-specific molecular pathways and drug therapies directed specifically at the cancer as it is expressed in each person. The concept of precision oncology is rapidly becoming integral to clinical practice. Many of these new agents are oral medications, which leads to increased ease of administration for the patient as well as decrease health care costs.²

In addition to targeted agents, major advancements have been made in cancer immunotherapy. The concept of using the immune system to fight malignancy has been around since the 19th century. In 1891, American surgeon William Coley retrospectively demonstrated improved outcomes in patients with inoperable sarcoma who had concomitant erysipelas infections.³ The principles of Coley’s theory were shown to be correct in 1959 when Old and colleagues determined the effectiveness of the bacterium Bacillus Calmette-Guérin (BCG) for treatment of superficial bladder cancer in mouse models.^4,5

The important role of the immune system in neoplastic growth and immunosuppression is now recognized as a risk factor for development of malignancy. Immune checkpoint inhibitors (ICI) such as pembrolizumab and nivolumab have changed practice in the solid tumor setting. Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical success in patients with hematologic cancers such as leukemia and lymphoma.^4,5

For the pharmacist considering a career shift to health-system pharmacy or oncology pharmacy in particular, this new world of cancer immunotherapy can be challenging. This program reviews recent developments in oral targeted therapy and describes advancements in CAR T-cell for treatment of relapsed/refractory (r/r) hematologic malignancies.

Fibroblast Growth Factor Receptor INHIBITORS

Bladder (urothelial carcinoma) and biliary tract (cholangiocarcinoma) cancers are very different diseases, often treated by separate medical oncology disciplines. However, these cancers share commonalities in their genetic heterogeneity, lack of second-line options in the metastatic stage, and poor prognosis. In patients with bladder cancer who are ineligible or have progressed after platinum-based therapy, second-line options for locally advanced or metastatic disease include immune checkpoint inhibitors (ICIs).⁶ Despite some durable responses, subsets of patients with variable programmed death ligand 1 (PD-L1) positivity, microsatellite instability (MSI) status, and histological subtypes fail to respond to ICI therapy. Recent data examining urothelial carcinoma (UC) gene profiles have demonstrated that luminal subtype 1 is associated with poor response to ICIs but a high percentage of mutations in the fibroblast growth factor receptor (FGFR).⁷

In metastatic cholangiocarcinoma, second-line options after progression on platinum-based chemotherapy provide minimal benefit.^8,9 Second-line options including oxaliplatin and 5-fluorouracil in patients previously treated with cisplatin and gemcitabine demonstrating only symptomatic benefit.¹⁰ Pembrolizumab, an ICI, demonstrated only modest responses in patients with cholangiocarcinoma that has MSI-H or deficient mismatch repair (dMMR) signals.⁹ Similar to bladder cancer, a high degree of genetic heterogeneity led to the discovery of FGFR alterations found almost exclusively in patients with intrahepatic cholangiocarcinoma, making it potential on target option.¹¹

Biology/Mechanism of Action

FGFRs are transmembrane proteins involved in the regulation of vitamin D and phosphate balance within a cell.¹² FGFR activation leads to downstream cellular proliferation, survival, and migration via mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathway.^12,13 FGFR3 alterations have been reported in approximately 20% of metastatic UCs and 10% to 16% of metastatic intrahepatic cholangiocarcinomas.^8,14 Erdafitinib demonstrated potent in vitro inhibition of FGFR1, FGFR2, FGFR3, and FGFR4 and demonstrated antitumor activity in corresponding mouse models.¹⁵ Pemigatinib demonstrated potent inhibition of FGFR1-3 but weak inhibition of FGFR4. Antitumor activity in mouse models with pemigatinib correlated with in vitro activity in FGFR1-3 but not FGFR4.¹⁶

Erdafitinib in Bladder Cancer

Erdafitinib was approved in April 2019 for the treatment of locally advanced of metastatic urothelial carcinoma with FGFR2 or FGFR3 genetic alterations following platinum-containing chemotherapy based on phase 2 study, BLC2001 (Table 1).¹⁷ In this groundbreaking, open-label phase 2 trial, 99 patients with FGFR3 mutation or FGFR2/3 fusion were assigned to intermittent dosing (10 mg/day, 7 days on, 7 days off) or continuous dosing (6 mg/day) until disease progressions or toxicity. After further pharmacokinetic modeling, the regimen was amended to continuous dosing (8 mg/day with provision to increase to 9 mg/day).¹⁸

The primary end point was confirmed response rate (RR). Secondary endpoints included progression-free survival (PFS), response duration, and overall survival (OS), safety, and response in biomarker specific subgroups. After a median duration of follow up of 11 months, the study demonstrated a 40% objective response rate. Within responders, 3% had complete response (CR) and 37% had partial response (PR). Median time to response and duration of response was 1.4 and 5.6 months, respectively. In terms of secondary endpoints, median PFS was 5.5 months and median OS was an impressive 13.8 months.¹⁸ In FGFR mutations and fusion subgroups, response rates were 49% and 16%, respectively.

Pemigatinib in Biliary Cancer

Based on outcomes from the FIGHT-002 clinical trial, pemigatinib was granted approval by the U.S. Food and Drug Administration (FDA) for the treatment of adults with locally advanced unresectable or metastatic cholangiocarcinoma with FGFR2 fusion or other rearrangements as detected by an FDA-approved test (Table 1).¹⁹ In this open-label, single-arm, phase 2 trial, 146 patients with carcinomas with FGFR2 fusions, FGF/FGFR alterations, or no alterations received pemigatinib 13.5 mg/day (2 weeks on/1 week off during a 21-day cycle).

The primary endpoint was proportion of patients with FGFR2 fusions or rearrangements who achieved an objective response (OR).²⁰ Secondary endpoints included the objective response rate (ORR) in FGF/FGFR other alterations, all patients with FGF/FGFR alterations, and in patients with no FGF/FGFR alterations, and duration of response, disease control rate (DCR), PFS, safety, and OS. Overall median follow-up was 17.8 months demonstrating an OR of 35.5% in participants with FGFR2 fusions. Within responders, 32.7% achieved a PR and 2.8% achieved a CR. Median duration of response, PFS, and OS in FGFR2 fusions positive patient was 7.5, 6.9, and 21.1 months, respectively. In other FGF/FGFR and no FGF/FGFR alterations groups, 40% and 22.2% achieved (best response) stable disease. PFS and OS in the other and no alterations groups were significantly less than in FGFR2 fusion arm.

Erdafitinib and Pemigatinib Toxicity

Overall, erdafitinib has been well tolerated with proper management and follow-up.²¹ Common adverse reactions (≥20% of patients) were increased phosphate, stomatitis, fatigue, increased creatinine, diarrhea, dry mouth, onycholysis, increased alanine aminotransferase (ALT), increased alkaline phosphatase, hyponatremia, decreased appetite, decreased albumin, dysgeusia, decreased hemoglobin, dry skin, increased aspartate aminotransferase (AST), hypomagnesemia, dry eye, alopecia, palmar-plantar erythrodysesthesia, constipation, hypophosphatemia, abdominal pain, hypercalcemia, nausea, and musculoskeletal pain. Clinically significant adverse events include ocular disorders such as central serous retinopathy/retinal pigment epithelial detachment and hyperphosphatemia. Serious adverse events included 1 patient who died of acute myocardial infarction. Dose interruptions and dose reductions occurred in 68% and 53% of patients, respectively, during erdafitinib therapy.

Pemigatinib demonstrated a similar safety profile compared to erdafitinib.²² Common adverse reactions (≥20%) are hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin. Serious adverse events include hyperphosphatemia with soft tissue mineralization and ocular toxicity with retinal pigment epithelial detachment. Fatal adverse events occurred in 4.1% of patients; causes included failure to thrive, biliary obstruction, cholangitis, sepsis, and pleural effusion. Dose interruptions and reductions occurred in 43% and 14% of patients, respectively, during pemigatinib therapy.

Conclusion

The FGFR inhibitors erdafitinib and pemigatinib provide second-line options in a niche molecular subset of patients with bladder and biliary tract cancers, respectively. As oral targeted agents, FGFR inhibitors are thought of as less toxic than intravenous chemotherapies. Providers and patients often let their guards down despite the risk of severe toxicities. Pharmacists in every setting, including those in clinics and community pharmacies, have the opportunity to optimize patient care and prevent severe toxicities through molecular profiling, management of hyperphosphatemia, over-the-counter recommendations for treating dry eyes, and follow-up reminders to prevent severe ocular disorders (Tables 2 and 3).

Rearrangement During Transfection INHIBITORS

Molecules targeting rearrangement during transfection (RET)–altered non-small cell lung cancer (NSCLC) and medullary thyroid carcinoma (MTC) remains an unfilled space. Patients with metastatic medullary thyroid cancer have an overall 5-year OS of 28%.²³ Current treatments for metastatic MTC include with radio-iodine therapy and targeted therapies such as cabozantinib and vandetinib, which have a variety of off-target toxicites.²⁴ In a long-term analysis, cabozantinib in patients with RETM18T mutation demonstrated a doubling of OS, while patients without RETM18T mutation did not fare better compared with placebo.²⁵ Vandetinib produced OS and PFS benefit compared with placebo, but cardiotoxicity restricts access through a Risk Evaluation and Mitigation Strategy (REMS) program.²⁶

Targeted therapies for NSCLC have been more fruitful, with incremental advances with each new drug approval. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies now have a longer 5-year survival rates ranging from 15% to 50%, depending on biomarker.²⁷ Mortality rates are declining, but there are still more deaths from lung cancer than from prostate, breast, colorectal, and brain cancers combined.²⁷ The recently approved next-generation RET inhibitors pralsetinib and selpercatinib help fill an unmet need in a subset of RET-altered MTC and add to the NSCLC armamentarium.

Biology/Mechanism of Action

The RET gene encodes a transmembrane receptor tyrosine kinase that is involved in normal embryonic development.²⁴ Various fusions between gene sequences lead abnormal RET expression and active ligand-dependent signaling and downstream oncogenesis.²⁸ Aberrant activation of the RET receptor has been associated with multiple endocrine neoplasia 2 (MEN2), an autosomal dominant cancer predisposition syndrome consisting of 3 primary tumors: medullary thyroid carcinoma, pheochromocytoma, and parathyroid carcinoma or adenomas.²⁹

Sporadic RET fusions have been identified in 1% to 2% of NSCLC and germ-line RET alterations (mutations or fusions) have been identified in 25% of patients with hereditary MTC.^30,31 Of the remaining 75% of patients with sporadic MTC, approximately 60% harbor somatic RET alterations.³¹ In early-phase studies, LOXO-292 (selpercatinib) and BLU-667 (pralsetinib) demonstrated 60–1300- and 10-fold more efficacy, respectively, in inhibiting KIF5B-RET fusion in cells lines compared with existing multikinase inhibitors.²⁹

Selpercatinib in Thyroid Cancer

Selpercatinib was granted FDA approval for patients 12 years of age or older with advanced or metastatic RET-mutant medullary thyroid carcinoma and RET fusion-positive thyroid cancer who are radioactive iodine-refractory who require systemic therapy based on the LIBRETTO-001 clinical trial (Table 1).³² In this clinical trial, patients 12 years of age or older with an identified RET mutation or fusion received doses ranging from 20 mg to 240 mg (phase 1 portion) or the recommended dose of 160 mg orally twice daily (phase 2 portion).³³

Overall, 162 patients were treated across 3 cohorts. In the cohort with RET-mutant MTC previously treated with vandetinib and cabozantinib (n = 55), ORR from independent review was 69%, with 9% achieving a CR and 60% achieving a PR.³³ Median follow-up in this cohort was 16.7 months with independently reviewed PFS ongoing. In the cohort with previously untreated RET-mutant (n = 88), independently reviewed ORR was 73%, with 11% and 61% achieving a CR and PR, respectively. Median follow-up was 11.1 months with a median PFS of 23.6 months assessed by independent review. In the third cohort of previously treated RET fusion-positive thyroid cancer (not MTC) (n = 19), independently reviewed OR was 79%, with 5% and 74% achieving a CR and PR, respectively. Median independently reviewed follow-up was 13.7 months, achieving a median PFS of 20.1 months.

Selpercatinib in Non-Small Cell Lung Cancer

In parallel, selpercatinib was also granted FDA approval for adult patients with RET fusion-positive NSCLC previously treated with platinum-based chemotherapy based on the LIBRETTO-001 phase 1–2 clinical trial (Table 1).³² In addition to patients with MTC, LIBRETTO-001 also enrolled 105 platinum-experienced and 39 previously untreated patients with RET fusion-positive NSCLC. In those previously treated with platinum chemotherapy, ORR by independent review was 64%, with 2% achieving CR and 65% achieving PR. Median duration of follow-up was 13.9 months, with median PFS of 16.5 months by independent review. In the previously untreated cohort, independently reviewed ORR was 85%, with all patients achieving a PR. Independently reviewed median follow-up was 9.2 months with median PFS ongoing.³⁴

In addition to positive systemic response, selpercatinib demonstrated central nervous system (CNS) activity in previously treated patients with NSCLC. In a small cohort (n = 11) of patients with measurable CNS disease, 10 patients demonstrated an ORR (3 CRs and 7 PRs).³⁴

Pralsetinib in Thyroid Cancer and NSCLC

Recently, a second RET inhibitor, pralsetinib, was approved by FDA for patients with RET-mutant thyroid cancer or RET fusion-positive NSCLC. Results from the recently presented ARROW phase 1/2 trial demonstrated similar ORRs of 60%, 66%, and 89% in 55 previously treated RET mutant, 29 treatment-naïve RET mutant, and 9 RET fusion-positive MTC patients, respectively.³⁵ In those with RET fusion-positive NSCLC, the ARROW trial demonstrated ORRs of 57% and 70% in platinum-experienced and treatment-naïve patients, respectively.³⁶ A small subset (n = 8) of patients with NSCLC and CNS disease at baseline demonstrated a 50% ORR, with 2 patients achieving a CR.³⁷

Selpercatinib and Pralsetinib Toxicity

Pooled LIBRETTO-001 clinical trial data showed that selpercatinib was well tolerated in patients with NSCLC, MTC, or thyroid cancer.³⁸ The most common adverse reactions (≥25% of patients) were increased AST, increased ALT, hyperglycemia, decreased leukocytes, decreased albumin, hypocalcemia, dry mouth, diarrhea, increased creatinine, hypertension, fatigue, edema, decreased platelets, hypercholesterolemia, rash, hyponatremia, and constipation. Serious adverse events include hepatotoxicity, hypertension, QT-interval prolongation, hemorrhage, tumor lysis syndrome (TLS), impaired wound healing, and hypersensitivity reactions. Fatal adverse events occurred in 3% of patients, including sepsis, cardiac arrest, and respiratory failure. Dose interruptions and dose reductions occurred in 42% and 31% of patients receiving selpercatinib, respectively.

Adverse events in the ARROW phase 1 /2 trial with pralsetinib were similar to with selpercatinib.³⁷ The most common adverse reactions (≥25%) were constipation, hypertension, fatigue, musculoskeletal pain, and diarrhea. The most common grade 3–4 laboratory abnormalities (≥2%) were decreased lymphocytes, neutropenia, decreased hemoglobin, hypophosphatemia, hypocalcemia, hyponatremia, increased AST, increased ALT, thrombocytopenia, and increased alkaline phosphatase. Serious adverse events included interstitial lung disease or pneumonitis, hypertension hepatotoxicity, TLS, and impaired wound healing. Fatal adverse events occurred in 5% of patients included pneumonia and sepsis. Dose interruptions and reductions occurred in 67% and 44%, respectively, of patients with thyroid cancer, and 60% and 36%, respectively, of patients with NSCLC.

Conclusion

Selpercatinib and pralsetinib are potent and selective inhibitors of RET in patients with defining mutations or fusions. Although not the first small molecules to inhibit RET, selpercatinib and pralsetinib have demonstrated superior on-target responses in MTC and thyroid cancer despite previous RET inhibition with vandetinib and cabozantinib or platinum-based chemotherapy. Limited off-target exposure means the drugs are well tolerated, unlike vandetinib, which requires REMS to monitor for cardiotoxicity.

In the NSCLC space, both selpercatinib and pralsetinib provided similar responses in treatment-naïve and platinum-experienced patients. In 2 studies, a small subset of patients with NSCLC demonstrated a CNS response.  Despite a better toxicity profile than other target therapies with RET sensitivity, close follow-up from oncology and medication therapy management pharmacists can prevent early severe toxicities such as hypersensitivity and hepatoxicity as well as help with management of chronic issues such as hypertension.

Neurotrophic Receptor Tyrosine Kinase INHIBITORS

The neurotrophic receptor tyrosine kinase (NTRK) inhibitors larotrectinib and entrectinib are members of a new class of small molecule anticancer agents billed as tissue-agnostic treatment options for all solid tumors. The second class of tissue-agnostic anticancer agents approved by FDA, they are indicated for adult and pediatric patients with NTRK gene-fusion-positive cancers.^39,40

Biology/Mechanism of Action

In common cancers, NTRK gene fusions are extremely rare, occurring in 0.1% to 2% of patients.⁴¹ However, there is widespread variability in this incidence and bias depending on the type of test used for NTRK gene fusions with common cancers such as colorectal, melanoma, sarcomas, cholangiocarcinomas, gliomas, appendiceal, and lung cancers (reported incidence of <5%). In certain exceedingly rare tumors such as pediatric infantile fibrosarcomas, adult salivary gland tumors, and secretory breast cancers, the incidence of NTRK gene fusion is much higher (>75%).⁴¹ Other rare tumors such as thyroid carcinomas — congenital mesoblastic nephromas and spitzoid melanomas — have reported incidences of 5%–75%, illustrating testing bias and variability in clinical laboratory technique.⁴¹ With currently available technologies, detecting an NTRK gene fusion signal can be challenging but provide long-term benefit.

Entrectinib in NTRK Fusion–Positive Cancers

Entrectinib was approved based on early-phase pooled analysis of 3 studies, the STARTRK-1, STARTRK-2, and ALKA-372-001 trials; these included 54 adult patients with NTRK fusion- positive metastatic or advanced tumors with or without brain metastasis (Table 3). Results demonstrated a high ORR of 57.4% (95% CI, 43.2–70.8) with 7.4% of patients achieving a CR.⁴⁰ Median duration of response was 10.4 months (95% CI, 7.1–not reached [NR]), PFS was 11.2 months (95% CI, 8–14.9), and median OS was 20.9 months (95% CI, 14.9–NR).⁴²

In adult patients with brain metastasis (n = 12) across the 3 studies, ORR was consistent with patients without brain metastasis at 50% with median PFS of 7.7 months (95% CI, 4.7–NR).⁴² Additionally, intracranial ORR was 54.5% in patients with baseline CNS disease, demonstrating entrectinib’s activity across the blood-brain barrier.⁴²

Pediatric approval (≥12 years old) of entrectinib was based on extrapolated adult data and early results from the phase 1/1b study STARTRK-NG, which enrolled 29 patients with primary CNS tumors, neuroblastomas, and other solid tumors with NTRK fusions, ROS1 fusions, or ALK fusions. Of 6 patients with CNS tumors, 1 patient achieved a CR, 3 patients achieved a PR, and 2 patient responses were yet to be confirmed.⁴³ Of 8 patients with extracranial solid tumors, 6 patients responded, including 2 patients with ALK fusion (CR and PR), 3 with NTRK fusion (PR), and 1 with ROS1 fusion (PR). Median time to response was 57 days (30–58 days).⁴³

Larotrectinib in NTRK Fusion-Positive Cancers

Larotrectinib was approved based on 3 phase 1 studies, the LOXO-TRK-14001, SCOUT, and NAVIGATE trials, involving 55 adults and children with NTRK fusion–positive tumors (Table 3). Eligible patients had locally advanced or metastatic disease who had exhausted standard of care treatments. Of the 55 patients, 17 unique cancer diagnoses were identified; the majority of patients (n = 30) had salivary gland tumors, pediatric fibrosarcomas, or other soft-tissue sarcomas. Additionally, only 1 patient had evidence of CNS metastasis in the pooled data.⁴⁴

At primary data-cut off, the overall response rate by independent radiologic review was 75% (95% CI, 61–85). A total of 13% of patients had CR, 62% had PR, 13% had stable disease, and 9% had progressive disease.⁴ The median duration of response  and PFS had not been reached after median follow-up duration of 8.3 and 9.9 months, respectively. At 1 year, 71% of responses were ongoing and 55% remained progression free.⁴⁴

Entrectinib and Larotrectinib Toxicity

Examining the safety profile of entrectinib from STARTRK-1, STARTRK-2, STARTRK-NG, and ALKA-372-001 trials, entrectinib was well tolerated in patients with NTRK fusion and ROS1 and ALK mutation–positive tumors. Of note, adverse events experience in pediatric patients may differ; most adverse event data comes from pooled adult trials.⁴⁵

The most common adverse reactions with entrectinib (≥20% of patients) were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia, and vision disorders. Clinically significant adverse events include congestive heart failure, CNS effects, skeletal fractures, hepatotoxicity, hyperuricemia, QT prolongation, and vision disorders. Fatal events included dyspnea, pneumonia, sepsis, suicide, intestinal perforation, and TLS. One patient experienced a grade 4 myocarditis that resolved. Dose interruptions and reductions occurred in 46% and 29% of patients, respectively.⁴⁵

Examining adverse events from LOXO-TRK-14001, SCOUT, and NAVIGATE trials, overall larotrectinib was well tolerated. The most common (>20%) adverse reactions, with larotrectinib were increased AST, increased ALT, anemia, musculoskeletal pain, fatigue, hypoalbuminemia, neutropenia, increased alkaline phosphatase, cough, leukopenia, constipation, diarrhea, dizziness, hypocalcemia, nausea, vomiting, pyrexia, lymphopenia, and abdominal pain. Clinically significant adverse events include CNS effects, skeletal fractures, and hepatotoxicity. Adverse events leading to dose reductions and interruptions occurred in 39% and 8% of patients, respectively.⁴⁶

Conclusion

Positive early-phase studies have demonstrated high response rates and durable responses with larotrectinib and entrectinib in adult and pediatric patients with NTRK gene fusions. Although NTRK alterations are rare in the general populations, a handful of tumors have a disproportionate share of NTRK gene fusion. Looking to the future, long-term follow-up and more extensive studies are needed to determine differences in safety and efficacy between larotrectinib and entrectinib in both pediatric and adult populations. Currently, adult and pediatric pharmacists in all solid tumor subspecialties should assess for the opportunity to advocate for NTRK gene fusion testing.

CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY

Cancer immunotherapy is being driven by ICIs and CAR T-cell therapy.⁴ While ICIs such as pembrolizumab and nivolumab have been practice changing in the solid tumor setting, their role for hematologic malignancies has been less important. CAR T-cell therapy has shown more promising results in heavily pretreated patients with different hematologic malignancies.

The principle of CAR T-cell therapy is to genetically re-engineer a patient’s own immune cells to boost the body’s immune response toward malignant cells. Currently, five CAR T-cell products are commercially available: tisagenlecleucel (Kymriah, CTL019), axicabtagene ciloleucel (Yescarta, KTE-C19), lisocabtagene maraleucel (Breyanzi, JCAR019), brexucabtagene autoleucel (Tecartus, KTE-X19), and idecabtagene vicleucel (Abecma, bb2121) (Table 7).^47–51 With other CAR T-cell products in the pipeline, pharmacists must understand their role in therapy as well as how to recognize and manage CAR T-cell–related toxicities.

Design/Mechanism of Action

CAR T-cells are engineered from the patient’s own T-cells to express artificial receptors that target tumor-specific antigens and augment T-cell function. Unlike T cell receptors that must bind to major histocompatibility complex (MHC) for antigen processing and T cell activation, CAR T-cells are able to bind directly to tumor-associated antigens in a non-MHC–dependent fashion.⁵² This increases the utility of CAR T-cells since tumor cells often downregulate MHC proteins to evade the immune system.

The CAR comprises the extracellular antigen recognition domain, the hinge domain, the transmembrane domain, and the intracellular signaling domain (Figure 1). The extracellular domain for CAR-T cells is made up of short-chain variable fragments (scVf) of antibodies and allows for tumor-antigen specificity. Initial CAR constructs had a single T-cell activating domain (CD3x) but had limited signaling capability and poor T-cell expansion. The second and third generation CAR-T cells have incorporated additional intracellular costimulatory signals (such as CD28 or 4-1BB) to improve both clinical response and T-cell persistence.^4,52 It is unclear if either co-stimulatory region has improved clinical outcomes, but CD28-based CAR constructs promote greater T-cell expansion while 4-1BB CARs have longer persistence.⁵³

Once the patient’s T-lymphocytes have undergone leukapheresis, they are sent to a centralized manufacturing laboratory for customization. There, the T cells are activated, transduced with a viral vector encoding the CAR gene, expanded in culture, and formulated to make the final CAR T-cell product (Figure 2). This process may take 17–24 days, depending on the CAR T-cell product.^47–51

Brexucabtagene autoleucel is identical to axicabtagene ciloleucel with CD28 as the costimulatory domain. The only difference between the products is that brexucabtagene autoleucel undergoes T-cell enrichment during the manufacturing process that removes circulating CD19-expressing malignant cells to reduce risk of production failure.

Tisagenlecleucel, lisocabtagene maraleucel, and idecabtagene vicleucel use a 4-1BB co-stimulation domain. The lisocabtagene maraleucel construct differs from the other CAR T-cell products in that it separately transduces and expands CD4+ and CD8+ T cells, which are then administered sequentially to the patient in a 1:1 fixed ratio. In vitro administration of CD4+/CD8+ CAR T-cells in a defined ratio optimizes antitumor efficacy as well as improves CAR T-cell expansion and persistence.⁵⁴

Patients receive lymphodepleting (LD) chemotherapy prior to CAR T-cell infusion to eliminate innate immunosuppressive elements such as regulatory T-cells and promote expansion, function, and persistence of CAR T-cells.⁵⁵ Fludarabine and cyclophosphamide are combined in the most commonly used regimen for LD chemotherapy, but patients receiving tisagenlecleucel may also receive bendamustine. A few days following LD chemotherapy, the CAR T-cells are reinfused into the patient, where they bind to the target antigen and stimulate a T-cell response against the antigen-expressing cell.

CAR T-Cells in Hematologic Malignancies

Currently, CAR T-cell therapy has demonstrated its greatest benefit in B-cell malignancies, such as acute lymphoblastic leukemia (ALL) or NHL. B-cell malignancies express several conserved cell surface markers. CD19 is an extracellular transmembrane glycoprotein that is the most common target for CAR T-cell constructs. CD19 is expressed on benign and most malignant B cells but has limited non B-cell expression making it an ideal target.⁵⁶ Another benefit of treating B-cell malignancies is that CAR T-cells readily migrate to areas that malignant cells will also accumulate, thus allowing easy access the target cells.

B-Cell ALL

Patients with r/r ALL have a challenging disease with poor outcomes. For pediatric patients, the 5-year survival rates are 30% to 50% after first relapse and less than 20% in those with multiple relapses; the 5-year survival rate in adult patients with r/r ALL is 40%.^57,58

CAR T-cell therapy offers a treatment option in the difficult-to-treat populations. The first commercially available CAR T-cell was tisagenlecleucel. It was approved by FDA for treatment of patients up to 25 years of age with B-cell ALL that is refractory or in second or later relapse.⁴⁷ Its approval was based on the ELIANA study, which was a multicenter phase 2 study that enrolled 97 children or young adults between 3 and 24 years of age with relapsed or refractory B-cell ALL.^59,60 Notable in this study population was the high number of patients who had previously received an allogeneic stem cell transplant (61%) and who were heavily pretreated.

In an updated analysis, the ORR for 79 patients who received tisagenlecleucel was 82% (95% CI, 72–90 months), with 65 patients achieving CR or CR with incomplete hematologic recovery (CRi). Of patients who had CR/CRi, 98% were minimal residual disease (MRD) negative. The median OS was not reached, but OS probability at 18 months was 70% (95% CI, 58–79). Median duration of response was not reached and relapsed free survival at 18 months was 66% (95% CI 52–77). This study also demonstrated the feasibility of global CAR-T manufacturing to broaden the access of this therapy beyond limited centers.^59,60

B-Cell NHL

Patients who have r/r B-cell NHL have poor outcomes following failure of immunochemotherapy or autologous stem cell transplant; In patients with r/r DLBCL, ORR to salvage therapy was 26% and median overall survival was 6.3 months.⁶¹ The use of CAR T-cell therapy in this setting serves a significant unmet need.

Axicabtagene ciloleucel was the first CAR T-cell product approved by the FDA for treatment of r/r B-cell lymphoma.⁴⁸ Its efficacy was evaluated in the multicenter ZUMA-1 trial, which was a phase 1/2 study in patients with r/r large B-cell lymphoma who had failed at least 2 prior lines of therapy and were considered to be chemotherapy refractory.⁶² Eligible subtypes included diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade lymphoma (with double-hit cytogenetics), and transformed follicular lymphoma (tFL). Of note, systemic bridging therapy was not allowed between leukapheresis and axicabtagene ciloleucel administration. The updated study phase II results showed an objective response rate of 83%, with 58% patients achieving CR. At 27.1-month median follow-up, 39% of participants had ongoing responses, including 37% with ongoing CR consistent across patient- and disease-specific cofactors. The median duration of response was 11.1 months and median PFS was 5.9 months. The median OS was not reached. The authors also noted that ongoing response at 24 months was associated with higher CAR T-cell peak concentrations.⁶²

The JULIET trial is a phase 2 multicenter global study that evaluated tisagenlecleucel in r/r large B-cell lymphoma at 27 treatment sites.^63,64 This study included patients who failed at least 2 lines of prior therapy and relapsed after or were ineligible for autologous transplantation. Unlike ZUMA-1, patients did not have to be chemotherapy refractory. Eligible lymphoma subtypes were similar to those included in ZUMA-1; however, this study excluded patients with PMBCL or patients who had active CNS involvement of DLBCL.

Of the 167 patients enrolled in the study, 115 received an infusion of tisagenlecleucel and 99 were eligible for assessment. The ORR was 54% (95% CI, 43–64%) with 40% CR; this response was seen across different prognostic subgroups. Median duration of response was not reached, and the median OS was 11.1 months (95% CI, 6.6 months–not reached).⁶³ Based on the results of the JULIET trial, the FDA granted approval for patients with r/r B-cell lymphoma.

Both the ZUMA-1 and JULIET trials have been criticized for having very strict patient selection criteria that are not representative of patients who may need CAR T-cell therapy in clinical practice. Since approval of these agents, retrospective analysis of axicabtagene ciloleucel and tisagenlecleucel in the real-world setting have been published that have shown rates of ORR similar to those in the pivotal trials.^65,66

The third CAR T-cell product approved for r/r B-cell lymphoma is lisocabtagene maraleucel. TRANSCEND NHL 001 is an open-label, multicenter phase 1 trial that evaluated lisocabtagene maraleucel in patients with DLBCL (including those transformed from indolent lymphoma), high-grade B-cell lymphoma (double- or triple-hit), PMBCL, or FL grade 3B. Patients with secondary CNS lymphoma were also eligible.⁶⁷

Of the 294 patients who received a CAR T-cell infusion across all dose levels, 269 patients received lisocabtagene maraleucel and 25 patients received a nonconforming product (release criteria not met for a single component but was deemed safe for infusion). At a median follow-up of 12 months, 256 patients who received lisocabtagene maraleucel showed 73% ORR (95% CI, 67–78) and CR achieved in 53% (95% CI, 26.8–59.4). The median duration of response was not reached, while the median PFS and OS were 6.8 months (95% CI, 3.3–14.1) and 21.1 months (95% CI,13.3–not reached), respectively. Among patients who achieved CR, median OS was not reached and OS was 86% (95% CI, 78.2–90.5) at 1 year.⁶⁷

Mantle Cell Lymphoma

Mantle-cell lymphoma (MCL) is a subtype of NHL with unique clinical and biologic features. In the relapsed setting, Bruton’s tyrosine kinase (BTK) inhibitors (ibrutinib and acalabrutinib) and Bcl-2 antagonists (venetoclax) are effective treatment options due to improved efficacy, durable responses, and increased tolerability compared with chemotherapy.⁶⁸

For patients who progress on BTK therapy, treatment options are limited and have poor prognosis. Brexucabtagene autoleucel is FDA approved in patients with r/r MCL and provides a novel option in this difficult to treat patient population.⁵¹

The efficacy of this CAR T-cell therapy was evaluated in the ZUMA-2 trial, an open-label, multicenter, phase 2 study in patients with r/r MCL. Participants had histologically confirmed MCL that was either relapsed or refractory to up to 5 previous regimens. During a median follow-up of 12.3 (range, 7.0–32.3) months, 60 evaluable patients had a 93% (95% CI, 84–98) ORR and 67% achieved CR. Median duration of response had not yet been reached, nor had the median PFS and OS. At 12 months, PFS and OS were 61% and 83%, respectively, and response was seen at 6 months among patients with poor prognostic features. This trial demonstrated brexucabtagene autoleucel could induce a durable response in patients with heavily pretreated MCL. It offers an option for this difficult-to-treat patient population.⁶⁹

Follicular Lymphoma

Follicular lymphoma (FL) is the most common indolent B-cell lymphoma. It has generally favorable outcomes and can have a long natural history. Patients with FL who have progression of disease within 24 months of diagnosis have poor outcomes and may not have adequate response to chemoimmunotherapy.⁷⁰

The use of CAR T-cell therapy has demonstrated very promising results in such patients. ZUMA-5 is a phase 2 multicenter study that evaluated the use of axicabtagene ciloleucel in patients with r/r FL or marginal zone lymphoma who had progressed after at least 2 lines of therapy. Among the 146 patients who received axicabtagene ciloleucel, 84 patients had FL. After a median follow-up of 17.5 (1.4–31.6) months, the ORR in the FL arm was 94%, and 80% of participants had CR. At the time of data cutoff, 64% of patients with FL had ongoing response and the medians for duration of response, PFS, and OS were not reached. Based on these data, the indication of axicabtagene ciloleucel was expanded to include patients with r/r FL who have failed 2 or more lines of systemic therapy.⁴⁸

Table 8 summarizes CAR T-cell use in patients with B-cell malignancies.

Multiple Myeloma

The treatment landscape of relapsed multiple myeloma (MM) has changed rapidly in the last few years due to the introduction of immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies. The development of these agents has improved the prognosis of MM significantly by increasing the depth of response.

Unfortunately, the majority of patients eventually relapse, and treatment in this setting is challenging. As the disease progresses, selecting effective therapies that will prolong OS becomes more difficult due to clonal evolution and development of drug resistance. There has been significant interest in developing a CAR-T cell product to target MM; however, the neoplastic plasma cells infrequently express CD19.^71,72

The B-cell maturation antigen (BCMA) is a transmembrane glycoprotein expressed preferentially on mature B-cell lymphocytes with minimal expression on hematopoietic stem cells or naïve B cells, making it an ideal target. Currently, many BCMA-targeted CAR T-cells are being studied, and the constructs differ between each product in terms of the make-up of each domain and manufacturing.

Idecabtagene vicleucel was the first anti-BCMA CAR T-cell therapy to gain FDA approval for patients with r/r MM who have failed at least 4 lines of prior therapy. Its approval was based on the KarMMa study, a phase 2 trial that included patients with r/r MM who progressed on at least 3 previous regimens.⁷³ A total of 140 patients were enrolled, and 128 received idecabtagene vicleucel. Despite being a heavily pretreated population (median 6 prior regimens), the ORR was 73% (95% CI, 66–81%) and 33% had a CR or higher. A higher CAR T-cell dose (>300 x 10⁶ cells) also yielded improved response rates. The median duration of response was 10.7 (95% CI, 10.3–11.4) months overall but slightly higher in patients who received a higher CAR T-cell dose (19 months). Patients who had deeper responses to idecabtagene vicleucel also had a longer response duration.⁷³

CAR T-Cell Therapy Toxicities

As treatment of the hematologic malignancies with CAR T-cell therapy expands, it is important to understand and recognize the unique acute and chronic toxicities of these agents. The incidence of CAR T-cell–associated toxicity is high, and some of these can be fatal if not managed appropriately.

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are two of the most commonly reported CAR T-cell–associated toxicities.^{59,60,62,63,69,70} As different CAR T-cell constructs were studied, CRS and ICANS definitions and grading varied greatly among the CAR T-cell products, which made toxicity comparisons between clinical trials difficult. In an effort to harmonize the classifications of immune effector cell–associated CRS and neurotoxicity, the American Society for Transplantation and Cellular Therapy (ASTCT) developed consensus guidelines on definitions and grading of CRS and ICANS.⁷⁴ Adoption of these definitions across all CAR T-cell clinical trials will help facilitate comparisons of safety profiles between the different CAR T-cell constructs.

The National Comprehensive Caner Network (NCCN) also provides guidance on how to manage CAR T-cell toxicities.⁷⁵ The NCCN guidance uses the ASTCT definitions and grading scales and also provides treatment and monitoring guidelines that are useful in clinical practice. By being familiar with these toxicities, pharmacists can play a role in prevention and management of complications of CAR T-cell therapy.

Cytokine Release Syndrome

CRS is the most commonly observed CAR T-cell–associated toxicity and can lead to potentially serious complications. The incidence of CRS has been reported in clinical trials ranged from 35% to 94%, depending on the CAR T-cell product, malignancy, and grading scale (Table 9).^47–51 The mechanism is likely due to a cytokine-mediated systemic inflammatory response following CAR T-cell activation from tumor recognition. This also activates bystander immune cells such as monocytes and macrophages to secrete large amounts of pro-inflammatory cytokines (IL-6, IL-10, IL-1) and inducible nitric oxide synthase (iNOS). Serum IL-6 levels have been correlated with severity of CRS and are highly elevated during CRS.⁷⁶

CRS commonly presents clinically with fevers, myalgias, hypotension, and hypoxia but can also manifest as renal failure, arrhythmias, pleural effusions, coagulopathy, and transaminitis. While CRS can be mild and reversible, it can also progress to hemodynamic compromise that requires vasopressor support and severe hypoxia requiring ventilator support. Table 10 outlines the CRS grading scale created by ASTCT.⁷⁴

Organ toxicity may also occur with CRS but does not influence CRS grading. Secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) can also result from overstimulation of immune function; it shares many of the same features as severe CRS. HLH/MAS often presents with fevers, elevated ferritin, elevated triglycerides, and IL-6. These abnormalities resolve when CRS resolves. The ASTCT guidelines do not treat HLH/MAS as a separate CAR T-cell–associated adverse event or include it with CRS grading.⁷⁴

CRS typically occurs during the first week (median, 2–3 days) following CAR T-cell infusion but can occur up to 58 days after cell infusion.^47–51 The typical duration is 7–8 days.⁷⁵ Patients receiving CAR T-cells with CD28 costimulatory domains have earlier onset of CRS compared with CAR T-cells with 4-1BB domains. Risk factors for more severe CRS include early onset of CRS (within 72 hours), high disease burden, fludarabine-based LD chemotherapy, and high CAR T-cell dose.⁷⁵

After patients have receive their CAR T-cell infusions, they should be monitored closely for signs and symptoms of CRS. Patients should be assessed for CRS and neurotoxicity twice daily during the periods of highest risk. C-reactive protein (CRP) and ferritin levels should be checked at baseline and rechecked at least 3 times weekly for 2 weeks after CAR T-cell infusions.⁷⁵ It is important to rule out other medical conditions such as neutropenic fever, sepsis, or adrenal insufficiency that may mimic CRS.⁷⁷

Immune Effector Cell–Associated Neurotoxicity Syndrome

Another unique toxicity seen with CAR T-cell therapy is neurotoxicity or ICANS. The incidence is variable based on CAR T-cell construct and underlying malignancy. ICANS typically manifests within 4–10 days following CART infusion, lasts 14–17 days, and may be accompanied by CRS or occur independently.⁷⁵

The presentation of neurotoxicity is diverse and not attributed to a specific location in the CNS.^77,78 Early symptoms include lethargy, confusion, tremors, expressive aphasia, and impaired attention. Patients may progress to more severe neurotoxicity symptoms, including seizures, motor weakness, loss of consciousness, and cerebral edema. Most symptoms of neurotoxicity are reversible, although fatal cases have been reported rarely. Patients with risk factors for developing severe CRS are also at higher risk for developing neurotoxicity. The symptoms of neurotoxicity may also differ based on the CAR T-cell product administered.⁷⁷

While the pathophysiology of ICANS is not well understood, patients with severe neurotoxicity have been found to have high serum levels of anti-inflammatory markers such as IL-6 and INF-g in the serum and cerebrospinal fluid. CAR T-cells have been detected in the cerebrospinal fluid even in the absence of CNS disease.⁷⁷

The ICANS grading scale was also redefined by ASTCT since each CAR T-cell product used a different grading system. ICANS assessment evaluates 5 neurologic domains, including presence of encephalopathy, level of consciousness, seizures, motor weakness, and raised intracranial pressure/cerebral edema. A screening tool, the Immune Effector Cell Associated Encephalopathy score, is used to provide objectivity to assessment of encephalopathy.^74,75

Treatment of CRS and ICANS

Prompt recognition and management of both CRS and ICANS is important to prevent serious toxicities. Patients should have frequent monitoring of vital signs, neurologic assessment, and laboratory values such as electrolytes, renal/hepatic function, blood count, and inflammatory markers. Patients who develop CRS may initially be managed with supportive care alone but may require vasopressor support if CRS worsens.⁷⁹

Tocilizumab is an anti-IL-6 receptor monoclonal antibody approved by FDA for management of severe or life-threatening CRS. It binds to both membrane-bound IL-6 receptor as well as soluble IL-6 receptor, which leads to a decrease in IL-6 signaling and reduction of immune activation. Administration of tocilizumab for CRS does not appear to affect clinical outcomes or serum CAR-T levels.^59,79,80

For patients who develop CRS, tocilizumab 8 mg/kg (maximum dose, 800 mg) may be administered and repeated every 8 hours as needed for a maximum of 4 doses. Each commercially available product has different criteria of when use of tocilizumab is appropriate. Brexucabtagene autoleucel and idecabtagene vicleucel product labeling recommends administration of tocilizumab for any grade of CRS, while tisagenlecleucel and axicabtagene ciloleucel product labeling recommends its use only in grade 2 CRS or higher.^47–51

Patients typically see symptom resolution within the first few days of tocilizumab administration, and the majority of CRS patients in the clinical trials required at least 1 dose. If patients do not show improvement within 12–24 hours following tocilizumab or have worsening of symptoms, concomitant corticosteroid (dexamethasone or methylprednisolone) administration is recommended.^47–51

For patients with grades 1 and 2 ICANS, the recommended treatment is supportive care along with an electroencephalogram to rule out seizures. Levetiracetam prophylaxis (500–750 mg orally every 12 hours for 30 days) should be considered in patients receiving CAR T-cell products with higher rates of ICANS. Use of pharmacologic agents that may exacerbate mental status changes, such as benzodiazepines or opiates, should be minimized. In those with concomitant CRS and ICANS, administration of tocilizumab is recommended.^47–51 However, tocilizumab is not recommended for neurotoxicity alone. Since tocilizumab binds to IL-6 receptors, administration of tocilizumab may lead to an influx of circulating IL-6, which can cross into the CNS and exacerbate neurotoxicity. In clinical trials, tocilizumab can reverse severe CRS, but has less impact on reversing the severity of neurotoxicity.⁷⁷

Corticosteroids are considered first-line therapy in patients with ICANS.⁷⁸ Dexamethasone or high-dose methylprednisolone may be used in those with grade 2 or higher ICANS. The impact of steroids on CAR T-cell efficacy and persistence has been a concern and published literature in patients who received steroids for CAR T-cell–associated toxicity have shown conflicting results in treatment outcomes or CAR T-cell expansion.^81,82 Providers may consider minimizing the duration of steroid therapy until more research has been published.

Patients who have grade 2 or higher neurotoxicity should be evaluated for cerebral edema using magnetic resonance imaging. Patients with cerebral edema should be treated promptly with high-dose corticosteroids to lower intracranial pressure.

There has been evidence in murine models that inhibition of IL-1 can prevent both CRS and ICANS without affecting CAR T-cell expansion. IL-1 triggers activation of monocytes, which produce IL-6 and thereby increase systemic inflammation. Anakinra is an IL-1 receptor agonist that is approved by FDA for treatment of patients with rheumatoid arthritis.⁸³ It is also beneficial in patients with secondary HLH, which can be seen concomitantly with CRS.⁸⁴ A small case series of 8 patients who received axicabtagene ciloleucel showed that administration of anakinra was beneficial in treatment of high-grade ICANS.⁸⁵ Ongoing phase 2 studies are further evaluating use of anakinra in this setting.

Given the incidence of CRS and ICANs, patients must be closely monitored after CAR T-cell infusion. All commercial CAR T-cell products have a REMS program, which is required by the FDA to ensure safe management of patients receiving this medication and decrease the risk of CRS and ICANS.^47–51 Key components of the CAR T-cell REMS program include ensuring that all personnel who prescribe, dispense, or administer CAR T-cells are aware of how to manage toxicities and that all patients have immediate access to tocilizumab following cell infusion. Lymphodepleting chemotherapy is generally given in the outpatient setting per the product labeling; axicabtagene ciloleucel and brexucabtagene autoleucel patients must be administered in a health care facility and monitored for toxicity for 7 days following CAR T-cell administration. Idecabtagene vicleucel may be administered either in the inpatient or outpatient setting; however, daily monitoring for 7 days following the CAR T-cell infusion is required. In clinical studies, tisagenlecleucel and lisocabtagene maraleucel have been administered CAR T-cell infusions successfully in the outpatient setting, but patients should be followed closely after infusion and hospitalized if patients experience toxicities.^59,67,86

Other CAR T-Cell–Associated Toxicities

Cytopenias are the most common toxicities seen after CAR T-cell therapy; these can persist for many weeks after CAR T-cell infusion.^47–51 The etiology of post-CAR T-cell cytopenia may be related to lymphodepleting chemotherapy, history of previous treatment, or cytokines released during CRS.

Because neutropenia is so commonly seen in CAR T-cell patients, prophylactic antimicrobials and antifungal agents should be considered. The FDA-approved product labeling for tisagenlecleucel specifically recommends against growth factor administration until 3 weeks after CAR T-cell infusion to decrease risk of CRS.⁴⁷ The decision to give filgrastim for the other CAR T-cell constructs is at the discretion of the provider.

Patient who receive fludarabine as part of their lymphodepleting chemotherapy should also receive herpes zoster and Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia prophylaxis for at least 1 year following CAR T-cell therapy. Chronic B cell aplasia and hypogammaglobulinemia is also seen post anti-CD19-CAR T-cell therapy. Since CD19 is expressed on most malignant and benign B cells, long-term CAR-T persistence leads to prolonged B-cell aplasia. For patients who have recurrent infections, immunoglobin replacement may be warranted in the setting of hypogammaglobulinemia.^78,79

Financial Implications

While CAR T-cells offer hope in the treatment of difficult-to-treat hematology malignancies, the economic burden of these therapies cannot be ignored. The wholesale acquisition cost of each agent range between $373,000 and $475,000, dependent on the CAR T-cell construct and the indication (Table 6).⁸⁷ Additional health care resources can contribute to overall costs, including leukapheresis, hospitalization to monitor for side effects, tocilizumab use, need for intensive-level care, and intravenous immunoglobulin use.⁸⁸

Cost savings are possible when CAR T-cell therapy is administered in the outpatient setting,⁸⁹ but this may not be a realistic option for oncology centers that do not have adequate outpatient facilities. Additionally, some of the CAR T-cell constructs require inpatient monitoring for 7 days following CAR T-cell infusion due to its shortened onset of CRS.

CONCLUSION

New cancer treatments are being developed at a rapid pace. Patient-centered care is driving oncology therapy away from the one-size-fits-all strategy of cytotoxic chemotherapy and introducing an era of targeting molecular pathways as well as harnessing the immune system. Pharmacists in health systems or oncology-based practices are well suited to be key resources in patient education about the new agents, emphasize medication adherence, manage toxicities, and provide supportive care.

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