Practical management of adverse events in patients receiving tarlatamab, a delta‐like ligand 3–targeted bispecific T‐cell engager immunotherapy, for previously treated small cell lung cancer
Tarlatamab is a bispecific T‐cell engager (BiTE) immunotherapy that binds both delta‐like ligand 3 (DLL3) on cancer cells and the cluster of differentiation 3 (CD3) molecule on T cells. Tarlatamab causes T‐cell activation, release of inflammatory cytokines, and lysis of DLL3‐expressing cells. Tarlatamab received accelerated approval from the US Food and Drug Administration in May 2024 for the treatment of patients with extensive‐stage small cell lung cancer (ES‐SCLC) who had disease progression on or after platinum‐based chemotherapy based on the durable responses and manageable safety profile observed in the DeLLphi‐301 phase 2 trial. , Here, we provide an overview of the safety profile of tarlatamab 10 mg with updated data from the DeLLphi‐301 trial (data cutoff, October 2, 2023). Details on the timing, occurrence, and duration of adverse events (AEs) are reported. We also provide clinical insights and strategies for AE management to optimize the long‐term patient treatment experience. OVERVIEW OF THE SAFETY PROFILE OF TARLATAMAB IN THE DeLLphi‐301 TRIAL In the phase 2 DeLLphi‐301 trial in patients with previously treated SCLC, 133 patients received at least one dose of tarlatamab 10 mg. The most common treatment‐emergent AEs (TEAEs; incidence, ≥20% of patients) were cytokine release syndrome (CRS; 53%), pyrexia (38%), decreased appetite (36%), dysgeusia (32%), anemia (30%), constipation (29%), asthenia (25%), and fatigue (24%; see Table ). Other TEAEs of interest were neutropenia (16%) and immune effector cell‐associated neurotoxicity syndrome (ICANS; 10%). The most common grade ≥3 TEAEs were lymphopenia (13.5%), anemia (8%), hyponatremia (6%), and neutropenia (6%; see Table ). The time to onset of key AEs from the first tarlatamab dose is illustrated in Figure . CRS, fatigue, and ICANS were observed early, whereas the onset of neutropenia was relatively delayed (Figure ). Treatment‐related AEs led to dose interruption in 15% of patients and discontinuation in 3% of patients. Cytokine release syndrome Given the mechanism of action of BiTE immunotherapies, the safety profile of tarlatamab includes CRS. , CRS is a systemic inflammatory response caused by the activation of T cells and the subsequent release of inflammatory cytokines, such as interferon gamma. CRS diagnosis has often been considered a diagnosis of exclusion. Fever is considered the defining symptom of CRS, which can evolve to present with hypoxia, hypotension, tachypnea, headache, tachycardia, and rash (see Table ). CRS can progress to include potentially life‐threatening complications and end organ damage. This presents a diagnostic challenge because the differential diagnosis of fever is broad and can be caused by other conditions, particularly in patients with cancer, including, but not limited to, infection, hypersensitivity, hemophagocytic lymphohistiocytosis, and tumor lysis syndrome. , , , CRS is graded using the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading criteria based on the presentation of fever and the severity of hypoxia and hypotension. It should be noted, however, that the incidence and severity of CRS are lower with BiTE therapies relative to chimeric antigen receptor T‐cell therapies. , , , , CRS in the DeLLphi‐301 trial In the DeLLphi‐301 trial, CRS occurred in 70 of 133 patients (53%) who received tarlatamab 10 mg (Table ). CRS predominantly occurred after the first or second tarlatamab dose. CRS was reported in 54 of 133 patients (41%) after the first dose and in 39 of 133 patients (29%) after the second dose (Figure ). Three of 133 patients (2%) experienced CRS at cycle 2 or later; each of these three patients had missed one or more doses during cycle 1 and had resumed treatment in cycle 2. The most common CRS symptom, other than fever, was hypotension (14 of 70 patients; 20%; Table ). CRS was predominantly grade 1 (42 of 70 patients; 60%) or grade 2 (fever with hypoxia and/or hypotension not requiring vasopressors; 27 of 70 patients; 39%), and one patient (1.4%) experienced grade 3 CRS (Table ). There were no grade 4 or 5 CRS events. The median time to CRS onset from the first tarlatamab dose was 13.7 hours (interquartile range [IQR], 9.3–33.2; Figure ). The median time to resolution (Kaplan–Meier estimate) was 3 days (IQR, 2–5 days). The median time to onset of grade ≥2 CRS from the last prior tarlatamab dose was 15.4 hours (IQR, 9.6–27.9 hours). Patients whose fever persisted for several hours, regardless of whether it subsided on antipyretic therapy, were more likely to experience a grade 2 or higher CRS event. Recurrent CRS occurred in 33 of 133 patients (25%). All patients with recurrent CRS had experienced their first CRS event during cycle 1. Recurrent CRS primarily occurred in cycle 1 and was grade 1 (88%) or grade 2 (12%; Table ). CRS led to dose interruption in four of 70 patients (6%). No patient discontinued tarlatamab because of CRS. One patient with concurrent grade 3 CRS died from respiratory failure. The respiratory failure was assessed by the investigator to be treatment‐related, although this categorization was confounded by the presence of other contributing factors, including baseline chronic obstructive pulmonary disease requiring supplemental oxygen, baseline compromised pulmonary functional reserve, concurrent grade 3 CRS and pneumonitis after cycle 1 day 1 (C1D1) treatment, and a decision against escalation to an intensive care unit level of care. CRS management in the DeLLphi‐301 trial When a patient presented with fever (≥38°C), a thorough work‐up to rule out other causes (infection or sepsis) was performed. If CRS was suspected, the CRS event was graded according to the ASTCT consensus grading and was treated based on the grade (Table ). , The management of CRS in the DeLLphi‐301 trial protocol is described in detail in Table . Of note, clinical trial sites were required to have medications for treating CRS available on site, including glucocorticoids and tocilizumab or siltuximab, if tocilizumab was not available. Because CRS in the DeLLphi‐301 trial was predominantly grade 1 or grade 2 in severity, it was generally managed with supportive care that included antipyretics (e.g., acetaminophen), intravenous hydration, and/or glucocorticoid use. Additional interventions, such as tocilizumab (used in eight of 70 patients), supplemental high‐flow oxygen (>6 liters per minute; one of 70 patients), and/or vasopressor support (one of 70 patients), were infrequently required (see Table ); siltuximab was not used. The incidence and duration of hospitalization for serious CRS are detailed in Table . Immune effector cell‐associated neurotoxicity syndrome The pathophysiology of ICANS remains poorly understood. Increased production of proinflammatory cytokines may lead to the activation of endothelial cells, increased permeability of the blood–brain barrier, and elevated levels of cytokines in the cerebrospinal fluid. Signs and symptoms vary and may include aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, and cerebral edema. According to the ASTCT grading system, ICANS is graded using a combination of the immune effector cell‐associated encephalopathy (ICE) score, level of consciousness, motor findings, seizure assessment, and intracranial pressure level or extent of cerebral edema (see Tables and ). ICANS is also a diagnosis of exclusion. Symptoms of ICANS can appear similar to symptoms observed with infection/sepsis, stroke, paraneoplastic syndromes, the use of pain medications, and new or progressive disease in the central nervous system. ICANS in the DeLLphi‐301 trial Because ICANS can have a wide range of manifestations with nonspecific symptoms, associated neurologic events were included in the reporting of ICANS (for the list of associated neurologic events, see Table ). In the DeLLphi‐301 trial, ICANS and associated neurologic events (henceforth referred to as ICANS) occurred in 13 of 133 patients (10%) who were treated with tarlatamab 10 mg (Table ). Patients with ICANS reported symptoms that included confusion, impaired attention, motor weakness/findings, dysgraphia, and increased tone (Table ). All ICANS events were grade 1 (seven of 13 patients; 54%) or grade 2 (six of 13 patients; 46%) in severity (Table ) and mostly occurred during cycle 1 or 2. (Figure ). Of the 13 patients with ICANS, the median time to onset from the first tarlatamab dose was 30 days (IQR, 13–47 days), and the median time to resolution was 33 days (IQR, 4–93 days; Kaplan–Meier estimate; Figure ). ICANS events that included confusion or impaired attention symptoms (11 of 16 events) were shorter in duration (median time to resolution, 8 days; IQR, 3–33 days), whereas ICANS events characterized by low‐grade muscular weakness symptoms (five of 16 events) generally took longer to resolve (median time to resolution, 69 days; IQR, 42 days to not estimable). ICANS led to dose interruption in one patient and discontinuation in one patient. No deaths from ICANS were reported. Two patients were hospitalized for serious ICANS after the first or second dose of tarlatamab, and two patients were hospitalized for serious ICANS after a third or later dose of tarlatamab. The frequency and duration of hospitalization for serious ICANS are detailed in Table . In a subgroup analysis, ICANS occurred in three of 22 patients (14%) with brain metastases and in five of 77 patients (6%) without brain metastases. All events were grade 1 or 2 in severity. ICANS management in the DeLLphi‐301 trial Patients in the DeLLphi‐301 trial were monitored for clinical signs or symptoms that could be suggestive of ICANS, including confusion, impaired attention, aphasia, tremor, and muscle weakness. It was important to rule out other neurologic etiologies, such as epilepsy, infectious disease, progression of central nervous system metastasis, side effects of other concomitant medications, or electrolyte disturbances within or outside the context of paraneoplastic syndromes. In the DeLLphi‐301 trial, neurologic examinations were performed as clinically indicated on or after dose administration. Although there were no grade 3 ICANS events in this trial, the protocol recommended a neurology consultation at the first sign of neurotoxicity and brain imaging for patients with persistent grade ≥3 neurotoxicity, with consideration for repeat neuroimaging (computed tomography or magnetic resonance imaging) every 2–3 days. Electroencephalograms were required for the assessment of any seizure activity that was grade ≥2. If ICANS was suspected, the next step involved using the ICE assessment tool (see Table ) and the ASTCT ICANS consensus grading criteria (see Table ). Management strategies for ICANS used in the DeLLphi‐301 trial are listed in Table . Briefly, grade 1 and 2 ICANS were to be managed by supportive care (grade 1) or steroids (grade 2). Steroids that were used included dexamethasone (10 mg intravenously), repeated every 6 hours if symptoms worsened, or methylprednisolone (1 mg/kg intravenously every 12 hours if symptoms worsened). For more severe events (grade ≥3) respiratory assistance with mechanical ventilation for airway protection (for grade 3 events) and treatment of status epilepticus according to institutional guidelines (for grade 4 events) were recommended, although this was never required in the DeLLphi‐301 trial (for details, see Table ). If grade ≥3 CRS with hypotension was also present, intravenous tocilizumab 8 mg/kg over 1 hour (not exceeding 800 mg per dose) was considered. STRATEGIES TO MITIGATE THE RISK OF DEVELOPING CRS AND ICANS USED IN THE DeLLphi‐301 TRIAL Pretreatment evaluation Before treatment in the DeLLphi‐301 trial, patients received physical and neurologic examinations and laboratory testing that included a complete blood count, blood chemistry panel testing, and quantitation of C‐reactive protein levels. Baseline hematologic, renal, hepatic, pulmonary, and cardiac functions were also assessed before the first dose of tarlatamab. Step‐up dosing Step‐up dosing involves starting with a lower dose and escalating to the target dose to gradually prime the immune system and reduce the risk and/or severity of CRS. In the DeLLphi‐301 trial, tarlatamab was administered as a step‐up dose of 1 mg on C1D1, followed by 10 mg tarlatamab on C1D8 and C1D15. Thereafter, patients received 10 mg tarlatamab every 2 weeks until they developed disease progression or unacceptable toxicity. If tarlatamab administration was delayed, the protocol defined restart guidelines for neurologic events, CRS, tumor lysis syndrome, nonfebrile neutropenia, pituitary gland dysfunction, and hepatotoxicity. For all other treatment interruptions and delays, the protocol outlined restart guidelines, as described in Table . Concomitant medications Prophylactic administration of corticosteroids has been shown to lower the incidence and severity of CRS and ICANS. , , In addition, intravenous hydration may prevent an escalation in the severity of CRS by offsetting the effects of any potential hypotension. In the DeLLphi‐301 trial, patients received intravenous dexamethasone 8 mg (or equivalent) within 1 hour before tarlatamab infusion on C1D1 and C1D8. Patients also received intravenous hydration (1 liter normal saline over 4–5 hours) immediately after all tarlatamab doses in cycle 1. Postinfusion monitoring For the dose‐evaluation (part 1) and dose‐expansion (part 2) parts of the DeLLphi‐301 trial, all patients received their C1D1 and C1D8 doses in the hospital and remained hospitalized for 48 hours for observation and AE monitoring. Hospitalization was not required on C1D15 unless the patient had experienced any grade CRS or neurologic events after the C1D1 or C1D8 doses; otherwise, the patient was observed for 8 hours after infusion (Table ). The frequency at which vital signs were assessed during hospitalization is detailed in Table . Hospitalization requirements from treatment cycle 2 and later are detailed in Table . In part 3—the reduced hospitalization substudy—patients were monitored for 24 hours (at either an inpatient unit or an outpatient infusion center) after the first two doses of tarlatamab (on C1D1 and C1D8). Vital signs were assessed as indicated in Table . Patients who experienced grade ≥2 CRS or grade ≥1 ICANS after the C1D1 and C1D8 infusions had increased additional hospitalization requirements. Patients were observed for 6–8 hours if they were not hospitalized. CRS was graded and treated as described previously and as indicated in Table . The safety profile in patients who were monitored for 24 hours postinfusion during cycle 1 was generally similar to that in patients who were monitored for 48 hours postinfusion. Posthospitalization requirements for the reduced hospitalization substudy Discharged patients were asked to stay within 1 hour of travel from the site for 48 hours and within 1 hour of a hospital for 72 hours after the C1D1 and C1D8 doses. A home companion was required for 72 hours after the C1D1 and C1D8 infusions. These considerations allowed for close monitoring, early detection of CRS, and prompt management if needed. Dysgeusia The neuroendocrine transcription factor ASCL1 drives the late‐stage differentiation of certain types of taste bud cells. Because ASCL1 also regulates DLL3 expression, it can be speculated that these taste bud cells express DLL3. Tarlatamab may lead to T‐cell–mediated destruction of these DLL3‐expressing taste bud cells, causing dysgeusia. In the DeLLphi‐301 trial, dysgeusia was reported in 42 of 133 patients (32%), with a median time to onset of 34 days (IQR, 21–51 days; Figure ). , Within the study protocol, no recommendations were provided for the management of dysgeusia. Some DeLLphi‐301 investigators used previously published strategies for managing dysgeusia. These strategies include nutritional counseling from a registered dietitian and maintenance of good oral dental hygiene (thorough brushing of teeth at least twice a day). Other published strategies include maintenance of adequate hydration by drinking a minimum of 1.5–2 liters of energy‐free beverages, such as water or unsweetened tea, per day; periodic chewing of cardamom; and inhaling the smell of cloves and lemon at least twice a day for about 15 seconds. Neutropenia Neutropenia is an identified risk for patients receiving tarlatamab. In the DeLLphi‐301 trial, treatment‐emergent neutropenia was reported in 21 of 133 patients (16%). Based on 21 patients who had events, the median time to onset of neutropenia was 56 days (IQR, 30–86 days; Figure ). Febrile neutropenia was reported in one of 133 patients (less than 1%). Neither neutropenia nor febrile neutropenia led to tarlatamab discontinuation. In the clinical trial setting, institution‐specific protocols were suggested for the management of grade 1 or 2 neutropenia. For grade ≥3 neutropenia, treatment interruption was suggested until the severity decreased to grade 2 or lower. The use of granulocyte‐colony–stimulating factor was permitted for the management of grade 3 neutropenia. Tarlatamab discontinuation was advised if an initial grade 3 nonfebrile neutropenia did not improve to grade 1 or lower within 3 weeks or if an initial grade 4 nonfebrile neutropenia lasted for >7 days or recurred at a lower dose level. Liver enzyme elevations An alanine aminotransferase (ALT) increase was observed in 15 patients (11.3%), and two patients (1.5%) experienced a grade 3 event. The median time to onset of ALT increase from the first tarlatamab dose was 29 days (IQR, 7–113 days). For the 14 patients (10.5%) who had increased aspartate aminotransferase (AST) levels, the median time to onset was 51 days (IQR, 3–196 days). One patient had elevated aminotransferase and total bilirubin greater than two times the upper limit of normal and alkaline phosphatase less than two 2 times the upper limit of normal. Elevated blood bilirubin was observed in four patients (3%). No patient reported tarlatamab discontinuation because of increased ALT or AST levels. The changes in liver enzyme and bilirubin levels were generally transient, with no evidence suggesting extensive hepatocellular damage. Documenting baseline levels of liver enzymes and bilirubin before starting tarlatamab and monitoring before each dose of tarlatamab and as clinically indicated was performed in the DeLLphi‐301 trial. Other TEAEs Other AEs reported in DeLLphi‐301 included decreased appetite, fatigue, anemia, and infections. Decreased appetite and fatigue are AEs that, if not appropriately monitored and managed, can negatively affect long‐term patient experience. In DeLLphi‐301, decreased appetite was reported in 48 of 133 patients (36%), and fatigue was reported in 32 of 133 patients (24%). Standard nonpharmacologic approaches, such as encouraging patients to undertake an optimal level of activity under the guidance of a health care provider, massage therapy, acupuncture, psychosocial interventions, nutrition consultations, and pharmacologic interventions, have been suggested for the management of fatigue in patients undergoing cancer treatment. Anemia was observed in 40 patients (30%), with a median time to onset of 13.0 days (range, 1–275 days) from the first tarlatamab dose. (Figure ). Among 57 patients with infections, the median time to onset was 37.0 days (range, 2–436 days). Grade ≥3 treatment‐emergent infections, including opportunistic infections, occurred in 17 of 133 patients (13%). The most frequent grade ≥3 treatment‐emergent infections were pneumonia ( n = 6), respiratory tract infection ( n = 3), device‐related infection, and pneumonia aspiration ( n = 2 each). Infections were managed using relevant institution‐specific protocols. For all infections, the prescribing information recommends withholding tarlatamab until resolution or, in the case of a grade 3 infection (graded according to Common Terminology Criteria for Adverse Events, version 5.0 guidelines ), withholding tarlatamab until infection improved to grade 1 or lower. Permanent discontinuation of tarlatamab was recommended in the case of a grade 4 infection. Considerations for patient management Early identification of the signs and symptoms of AEs and an awareness of management practices may help health care providers optimize care for patients who are receiving tarlatamab. Thus patients in the DeLLphi‐301 trial were monitored in a health care facility for 24–48 hours after the first two doses of tarlatamab. Investigators also took into consideration the ability to rapidly transfer patients to an intensive care unit to manage higher grade CRS or ICANS events. After hospital discharge, patients were to be accompanied by a caregiver and remain within 1 hour of an appropriate health care setting for a total of 72 hours postinfusion after the first two tarlatamab doses. Other considerations identified by investigators that can aid in optimizing the management of CRS and ICANS are listed in Table . Health care providers educated patients and caregivers on recognizing the signs and symptoms of CRS and ICANS. They were taught to recognize CRS symptoms, such as fever, difficulty breathing or unusual shortness of breath, headache, chest pain, palpitations, persistent nausea or vomiting, chills, and/or myalgia, and were advised on the appropriate administration of acetaminophen. Patients and caregivers were also instructed on monitoring changes in vital signs (body temperature [≥38°C], blood pressure, oxygen saturation, and heart rate) for the early identification of AEs. When a patient living in a rural setting developed symptoms suggestive of CRS, the patient and caregiver were instructed to treat with dexamethasone and visit the emergency room for further help. Patients and caregivers were also taught to recognize neurologic symptoms that could be manifestations of ICANS, such as headache, dysgeusia, dizziness, insomnia, muscular weakness, ataxia, amnesia, confusion, disorientation, and lethargy. They were instructed to call or see their treating health care provider right away or go to the emergency room if they experienced any neurologic symptoms at any time during their treatment with tarlatamab. Patients were also advised to refrain from driving, operating heavy or potentially dangerous machinery, and engaging in hazardous occupations or activities until their neurologic symptoms resolved. Patient or caregiver diaries with a descriptive record of symptoms, timing, and duration of AEs can assist health care providers with the management of AEs (Table ). In addition, at one site, patients and caregivers were provided wallet cards with key contact information and asked to show the wallet card to health care providers. 

In the phase 2 DeLLphi‐301 trial in patients with previously treated SCLC, 133 patients received at least one dose of tarlatamab 10 mg. The most common treatment‐emergent AEs (TEAEs; incidence, ≥20% of patients) were cytokine release syndrome (CRS; 53%), pyrexia (38%), decreased appetite (36%), dysgeusia (32%), anemia (30%), constipation (29%), asthenia (25%), and fatigue (24%; see Table ). Other TEAEs of interest were neutropenia (16%) and immune effector cell‐associated neurotoxicity syndrome (ICANS; 10%). The most common grade ≥3 TEAEs were lymphopenia (13.5%), anemia (8%), hyponatremia (6%), and neutropenia (6%; see Table ). The time to onset of key AEs from the first tarlatamab dose is illustrated in Figure . CRS, fatigue, and ICANS were observed early, whereas the onset of neutropenia was relatively delayed (Figure ). Treatment‐related AEs led to dose interruption in 15% of patients and discontinuation in 3% of patients. 

Given the mechanism of action of BiTE immunotherapies, the safety profile of tarlatamab includes CRS. , CRS is a systemic inflammatory response caused by the activation of T cells and the subsequent release of inflammatory cytokines, such as interferon gamma. CRS diagnosis has often been considered a diagnosis of exclusion. Fever is considered the defining symptom of CRS, which can evolve to present with hypoxia, hypotension, tachypnea, headache, tachycardia, and rash (see Table ). CRS can progress to include potentially life‐threatening complications and end organ damage. This presents a diagnostic challenge because the differential diagnosis of fever is broad and can be caused by other conditions, particularly in patients with cancer, including, but not limited to, infection, hypersensitivity, hemophagocytic lymphohistiocytosis, and tumor lysis syndrome. , , , CRS is graded using the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading criteria based on the presentation of fever and the severity of hypoxia and hypotension. It should be noted, however, that the incidence and severity of CRS are lower with BiTE therapies relative to chimeric antigen receptor T‐cell therapies. , , , , 

In the DeLLphi‐301 trial, CRS occurred in 70 of 133 patients (53%) who received tarlatamab 10 mg (Table ). CRS predominantly occurred after the first or second tarlatamab dose. CRS was reported in 54 of 133 patients (41%) after the first dose and in 39 of 133 patients (29%) after the second dose (Figure ). Three of 133 patients (2%) experienced CRS at cycle 2 or later; each of these three patients had missed one or more doses during cycle 1 and had resumed treatment in cycle 2. The most common CRS symptom, other than fever, was hypotension (14 of 70 patients; 20%; Table ). CRS was predominantly grade 1 (42 of 70 patients; 60%) or grade 2 (fever with hypoxia and/or hypotension not requiring vasopressors; 27 of 70 patients; 39%), and one patient (1.4%) experienced grade 3 CRS (Table ). There were no grade 4 or 5 CRS events. The median time to CRS onset from the first tarlatamab dose was 13.7 hours (interquartile range [IQR], 9.3–33.2; Figure ). The median time to resolution (Kaplan–Meier estimate) was 3 days (IQR, 2–5 days). The median time to onset of grade ≥2 CRS from the last prior tarlatamab dose was 15.4 hours (IQR, 9.6–27.9 hours). Patients whose fever persisted for several hours, regardless of whether it subsided on antipyretic therapy, were more likely to experience a grade 2 or higher CRS event. Recurrent CRS occurred in 33 of 133 patients (25%). All patients with recurrent CRS had experienced their first CRS event during cycle 1. Recurrent CRS primarily occurred in cycle 1 and was grade 1 (88%) or grade 2 (12%; Table ). CRS led to dose interruption in four of 70 patients (6%). No patient discontinued tarlatamab because of CRS. One patient with concurrent grade 3 CRS died from respiratory failure. The respiratory failure was assessed by the investigator to be treatment‐related, although this categorization was confounded by the presence of other contributing factors, including baseline chronic obstructive pulmonary disease requiring supplemental oxygen, baseline compromised pulmonary functional reserve, concurrent grade 3 CRS and pneumonitis after cycle 1 day 1 (C1D1) treatment, and a decision against escalation to an intensive care unit level of care. 

When a patient presented with fever (≥38°C), a thorough work‐up to rule out other causes (infection or sepsis) was performed. If CRS was suspected, the CRS event was graded according to the ASTCT consensus grading and was treated based on the grade (Table ). , The management of CRS in the DeLLphi‐301 trial protocol is described in detail in Table . Of note, clinical trial sites were required to have medications for treating CRS available on site, including glucocorticoids and tocilizumab or siltuximab, if tocilizumab was not available. Because CRS in the DeLLphi‐301 trial was predominantly grade 1 or grade 2 in severity, it was generally managed with supportive care that included antipyretics (e.g., acetaminophen), intravenous hydration, and/or glucocorticoid use. Additional interventions, such as tocilizumab (used in eight of 70 patients), supplemental high‐flow oxygen (>6 liters per minute; one of 70 patients), and/or vasopressor support (one of 70 patients), were infrequently required (see Table ); siltuximab was not used. The incidence and duration of hospitalization for serious CRS are detailed in Table . 

The pathophysiology of ICANS remains poorly understood. Increased production of proinflammatory cytokines may lead to the activation of endothelial cells, increased permeability of the blood–brain barrier, and elevated levels of cytokines in the cerebrospinal fluid. Signs and symptoms vary and may include aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, and cerebral edema. According to the ASTCT grading system, ICANS is graded using a combination of the immune effector cell‐associated encephalopathy (ICE) score, level of consciousness, motor findings, seizure assessment, and intracranial pressure level or extent of cerebral edema (see Tables and ). ICANS is also a diagnosis of exclusion. Symptoms of ICANS can appear similar to symptoms observed with infection/sepsis, stroke, paraneoplastic syndromes, the use of pain medications, and new or progressive disease in the central nervous system. 

Because ICANS can have a wide range of manifestations with nonspecific symptoms, associated neurologic events were included in the reporting of ICANS (for the list of associated neurologic events, see Table ). In the DeLLphi‐301 trial, ICANS and associated neurologic events (henceforth referred to as ICANS) occurred in 13 of 133 patients (10%) who were treated with tarlatamab 10 mg (Table ). Patients with ICANS reported symptoms that included confusion, impaired attention, motor weakness/findings, dysgraphia, and increased tone (Table ). All ICANS events were grade 1 (seven of 13 patients; 54%) or grade 2 (six of 13 patients; 46%) in severity (Table ) and mostly occurred during cycle 1 or 2. (Figure ). Of the 13 patients with ICANS, the median time to onset from the first tarlatamab dose was 30 days (IQR, 13–47 days), and the median time to resolution was 33 days (IQR, 4–93 days; Kaplan–Meier estimate; Figure ). ICANS events that included confusion or impaired attention symptoms (11 of 16 events) were shorter in duration (median time to resolution, 8 days; IQR, 3–33 days), whereas ICANS events characterized by low‐grade muscular weakness symptoms (five of 16 events) generally took longer to resolve (median time to resolution, 69 days; IQR, 42 days to not estimable). ICANS led to dose interruption in one patient and discontinuation in one patient. No deaths from ICANS were reported. Two patients were hospitalized for serious ICANS after the first or second dose of tarlatamab, and two patients were hospitalized for serious ICANS after a third or later dose of tarlatamab. The frequency and duration of hospitalization for serious ICANS are detailed in Table . In a subgroup analysis, ICANS occurred in three of 22 patients (14%) with brain metastases and in five of 77 patients (6%) without brain metastases. All events were grade 1 or 2 in severity. 

Patients in the DeLLphi‐301 trial were monitored for clinical signs or symptoms that could be suggestive of ICANS, including confusion, impaired attention, aphasia, tremor, and muscle weakness. It was important to rule out other neurologic etiologies, such as epilepsy, infectious disease, progression of central nervous system metastasis, side effects of other concomitant medications, or electrolyte disturbances within or outside the context of paraneoplastic syndromes. In the DeLLphi‐301 trial, neurologic examinations were performed as clinically indicated on or after dose administration. Although there were no grade 3 ICANS events in this trial, the protocol recommended a neurology consultation at the first sign of neurotoxicity and brain imaging for patients with persistent grade ≥3 neurotoxicity, with consideration for repeat neuroimaging (computed tomography or magnetic resonance imaging) every 2–3 days. Electroencephalograms were required for the assessment of any seizure activity that was grade ≥2. If ICANS was suspected, the next step involved using the ICE assessment tool (see Table ) and the ASTCT ICANS consensus grading criteria (see Table ). Management strategies for ICANS used in the DeLLphi‐301 trial are listed in Table . Briefly, grade 1 and 2 ICANS were to be managed by supportive care (grade 1) or steroids (grade 2). Steroids that were used included dexamethasone (10 mg intravenously), repeated every 6 hours if symptoms worsened, or methylprednisolone (1 mg/kg intravenously every 12 hours if symptoms worsened). For more severe events (grade ≥3) respiratory assistance with mechanical ventilation for airway protection (for grade 3 events) and treatment of status epilepticus according to institutional guidelines (for grade 4 events) were recommended, although this was never required in the DeLLphi‐301 trial (for details, see Table ). If grade ≥3 CRS with hypotension was also present, intravenous tocilizumab 8 mg/kg over 1 hour (not exceeding 800 mg per dose) was considered. 

Pretreatment evaluation Before treatment in the DeLLphi‐301 trial, patients received physical and neurologic examinations and laboratory testing that included a complete blood count, blood chemistry panel testing, and quantitation of C‐reactive protein levels. Baseline hematologic, renal, hepatic, pulmonary, and cardiac functions were also assessed before the first dose of tarlatamab. Step‐up dosing Step‐up dosing involves starting with a lower dose and escalating to the target dose to gradually prime the immune system and reduce the risk and/or severity of CRS. In the DeLLphi‐301 trial, tarlatamab was administered as a step‐up dose of 1 mg on C1D1, followed by 10 mg tarlatamab on C1D8 and C1D15. Thereafter, patients received 10 mg tarlatamab every 2 weeks until they developed disease progression or unacceptable toxicity. If tarlatamab administration was delayed, the protocol defined restart guidelines for neurologic events, CRS, tumor lysis syndrome, nonfebrile neutropenia, pituitary gland dysfunction, and hepatotoxicity. For all other treatment interruptions and delays, the protocol outlined restart guidelines, as described in Table . Concomitant medications Prophylactic administration of corticosteroids has been shown to lower the incidence and severity of CRS and ICANS. , , In addition, intravenous hydration may prevent an escalation in the severity of CRS by offsetting the effects of any potential hypotension. In the DeLLphi‐301 trial, patients received intravenous dexamethasone 8 mg (or equivalent) within 1 hour before tarlatamab infusion on C1D1 and C1D8. Patients also received intravenous hydration (1 liter normal saline over 4–5 hours) immediately after all tarlatamab doses in cycle 1. Postinfusion monitoring For the dose‐evaluation (part 1) and dose‐expansion (part 2) parts of the DeLLphi‐301 trial, all patients received their C1D1 and C1D8 doses in the hospital and remained hospitalized for 48 hours for observation and AE monitoring. Hospitalization was not required on C1D15 unless the patient had experienced any grade CRS or neurologic events after the C1D1 or C1D8 doses; otherwise, the patient was observed for 8 hours after infusion (Table ). The frequency at which vital signs were assessed during hospitalization is detailed in Table . Hospitalization requirements from treatment cycle 2 and later are detailed in Table . In part 3—the reduced hospitalization substudy—patients were monitored for 24 hours (at either an inpatient unit or an outpatient infusion center) after the first two doses of tarlatamab (on C1D1 and C1D8). Vital signs were assessed as indicated in Table . Patients who experienced grade ≥2 CRS or grade ≥1 ICANS after the C1D1 and C1D8 infusions had increased additional hospitalization requirements. Patients were observed for 6–8 hours if they were not hospitalized. CRS was graded and treated as described previously and as indicated in Table . The safety profile in patients who were monitored for 24 hours postinfusion during cycle 1 was generally similar to that in patients who were monitored for 48 hours postinfusion. 

Before treatment in the DeLLphi‐301 trial, patients received physical and neurologic examinations and laboratory testing that included a complete blood count, blood chemistry panel testing, and quantitation of C‐reactive protein levels. Baseline hematologic, renal, hepatic, pulmonary, and cardiac functions were also assessed before the first dose of tarlatamab. 

Step‐up dosing involves starting with a lower dose and escalating to the target dose to gradually prime the immune system and reduce the risk and/or severity of CRS. In the DeLLphi‐301 trial, tarlatamab was administered as a step‐up dose of 1 mg on C1D1, followed by 10 mg tarlatamab on C1D8 and C1D15. Thereafter, patients received 10 mg tarlatamab every 2 weeks until they developed disease progression or unacceptable toxicity. If tarlatamab administration was delayed, the protocol defined restart guidelines for neurologic events, CRS, tumor lysis syndrome, nonfebrile neutropenia, pituitary gland dysfunction, and hepatotoxicity. For all other treatment interruptions and delays, the protocol outlined restart guidelines, as described in Table . 

Prophylactic administration of corticosteroids has been shown to lower the incidence and severity of CRS and ICANS. , , In addition, intravenous hydration may prevent an escalation in the severity of CRS by offsetting the effects of any potential hypotension. In the DeLLphi‐301 trial, patients received intravenous dexamethasone 8 mg (or equivalent) within 1 hour before tarlatamab infusion on C1D1 and C1D8. Patients also received intravenous hydration (1 liter normal saline over 4–5 hours) immediately after all tarlatamab doses in cycle 1. 

For the dose‐evaluation (part 1) and dose‐expansion (part 2) parts of the DeLLphi‐301 trial, all patients received their C1D1 and C1D8 doses in the hospital and remained hospitalized for 48 hours for observation and AE monitoring. Hospitalization was not required on C1D15 unless the patient had experienced any grade CRS or neurologic events after the C1D1 or C1D8 doses; otherwise, the patient was observed for 8 hours after infusion (Table ). The frequency at which vital signs were assessed during hospitalization is detailed in Table . Hospitalization requirements from treatment cycle 2 and later are detailed in Table . In part 3—the reduced hospitalization substudy—patients were monitored for 24 hours (at either an inpatient unit or an outpatient infusion center) after the first two doses of tarlatamab (on C1D1 and C1D8). Vital signs were assessed as indicated in Table . Patients who experienced grade ≥2 CRS or grade ≥1 ICANS after the C1D1 and C1D8 infusions had increased additional hospitalization requirements. Patients were observed for 6–8 hours if they were not hospitalized. CRS was graded and treated as described previously and as indicated in Table . The safety profile in patients who were monitored for 24 hours postinfusion during cycle 1 was generally similar to that in patients who were monitored for 48 hours postinfusion. 

Discharged patients were asked to stay within 1 hour of travel from the site for 48 hours and within 1 hour of a hospital for 72 hours after the C1D1 and C1D8 doses. A home companion was required for 72 hours after the C1D1 and C1D8 infusions. These considerations allowed for close monitoring, early detection of CRS, and prompt management if needed. Dysgeusia The neuroendocrine transcription factor ASCL1 drives the late‐stage differentiation of certain types of taste bud cells. Because ASCL1 also regulates DLL3 expression, it can be speculated that these taste bud cells express DLL3. Tarlatamab may lead to T‐cell–mediated destruction of these DLL3‐expressing taste bud cells, causing dysgeusia. In the DeLLphi‐301 trial, dysgeusia was reported in 42 of 133 patients (32%), with a median time to onset of 34 days (IQR, 21–51 days; Figure ). , Within the study protocol, no recommendations were provided for the management of dysgeusia. Some DeLLphi‐301 investigators used previously published strategies for managing dysgeusia. These strategies include nutritional counseling from a registered dietitian and maintenance of good oral dental hygiene (thorough brushing of teeth at least twice a day). Other published strategies include maintenance of adequate hydration by drinking a minimum of 1.5–2 liters of energy‐free beverages, such as water or unsweetened tea, per day; periodic chewing of cardamom; and inhaling the smell of cloves and lemon at least twice a day for about 15 seconds. Neutropenia Neutropenia is an identified risk for patients receiving tarlatamab. In the DeLLphi‐301 trial, treatment‐emergent neutropenia was reported in 21 of 133 patients (16%). Based on 21 patients who had events, the median time to onset of neutropenia was 56 days (IQR, 30–86 days; Figure ). Febrile neutropenia was reported in one of 133 patients (less than 1%). Neither neutropenia nor febrile neutropenia led to tarlatamab discontinuation. In the clinical trial setting, institution‐specific protocols were suggested for the management of grade 1 or 2 neutropenia. For grade ≥3 neutropenia, treatment interruption was suggested until the severity decreased to grade 2 or lower. The use of granulocyte‐colony–stimulating factor was permitted for the management of grade 3 neutropenia. Tarlatamab discontinuation was advised if an initial grade 3 nonfebrile neutropenia did not improve to grade 1 or lower within 3 weeks or if an initial grade 4 nonfebrile neutropenia lasted for >7 days or recurred at a lower dose level. Liver enzyme elevations An alanine aminotransferase (ALT) increase was observed in 15 patients (11.3%), and two patients (1.5%) experienced a grade 3 event. The median time to onset of ALT increase from the first tarlatamab dose was 29 days (IQR, 7–113 days). For the 14 patients (10.5%) who had increased aspartate aminotransferase (AST) levels, the median time to onset was 51 days (IQR, 3–196 days). One patient had elevated aminotransferase and total bilirubin greater than two times the upper limit of normal and alkaline phosphatase less than two 2 times the upper limit of normal. Elevated blood bilirubin was observed in four patients (3%). No patient reported tarlatamab discontinuation because of increased ALT or AST levels. The changes in liver enzyme and bilirubin levels were generally transient, with no evidence suggesting extensive hepatocellular damage. Documenting baseline levels of liver enzymes and bilirubin before starting tarlatamab and monitoring before each dose of tarlatamab and as clinically indicated was performed in the DeLLphi‐301 trial. Other TEAEs Other AEs reported in DeLLphi‐301 included decreased appetite, fatigue, anemia, and infections. Decreased appetite and fatigue are AEs that, if not appropriately monitored and managed, can negatively affect long‐term patient experience. In DeLLphi‐301, decreased appetite was reported in 48 of 133 patients (36%), and fatigue was reported in 32 of 133 patients (24%). Standard nonpharmacologic approaches, such as encouraging patients to undertake an optimal level of activity under the guidance of a health care provider, massage therapy, acupuncture, psychosocial interventions, nutrition consultations, and pharmacologic interventions, have been suggested for the management of fatigue in patients undergoing cancer treatment. Anemia was observed in 40 patients (30%), with a median time to onset of 13.0 days (range, 1–275 days) from the first tarlatamab dose. (Figure ). Among 57 patients with infections, the median time to onset was 37.0 days (range, 2–436 days). Grade ≥3 treatment‐emergent infections, including opportunistic infections, occurred in 17 of 133 patients (13%). The most frequent grade ≥3 treatment‐emergent infections were pneumonia ( n = 6), respiratory tract infection ( n = 3), device‐related infection, and pneumonia aspiration ( n = 2 each). Infections were managed using relevant institution‐specific protocols. For all infections, the prescribing information recommends withholding tarlatamab until resolution or, in the case of a grade 3 infection (graded according to Common Terminology Criteria for Adverse Events, version 5.0 guidelines ), withholding tarlatamab until infection improved to grade 1 or lower. Permanent discontinuation of tarlatamab was recommended in the case of a grade 4 infection. 

The neuroendocrine transcription factor ASCL1 drives the late‐stage differentiation of certain types of taste bud cells. Because ASCL1 also regulates DLL3 expression, it can be speculated that these taste bud cells express DLL3. Tarlatamab may lead to T‐cell–mediated destruction of these DLL3‐expressing taste bud cells, causing dysgeusia. In the DeLLphi‐301 trial, dysgeusia was reported in 42 of 133 patients (32%), with a median time to onset of 34 days (IQR, 21–51 days; Figure ). , Within the study protocol, no recommendations were provided for the management of dysgeusia. Some DeLLphi‐301 investigators used previously published strategies for managing dysgeusia. These strategies include nutritional counseling from a registered dietitian and maintenance of good oral dental hygiene (thorough brushing of teeth at least twice a day). Other published strategies include maintenance of adequate hydration by drinking a minimum of 1.5–2 liters of energy‐free beverages, such as water or unsweetened tea, per day; periodic chewing of cardamom; and inhaling the smell of cloves and lemon at least twice a day for about 15 seconds. 

Neutropenia is an identified risk for patients receiving tarlatamab. In the DeLLphi‐301 trial, treatment‐emergent neutropenia was reported in 21 of 133 patients (16%). Based on 21 patients who had events, the median time to onset of neutropenia was 56 days (IQR, 30–86 days; Figure ). Febrile neutropenia was reported in one of 133 patients (less than 1%). Neither neutropenia nor febrile neutropenia led to tarlatamab discontinuation. In the clinical trial setting, institution‐specific protocols were suggested for the management of grade 1 or 2 neutropenia. For grade ≥3 neutropenia, treatment interruption was suggested until the severity decreased to grade 2 or lower. The use of granulocyte‐colony–stimulating factor was permitted for the management of grade 3 neutropenia. Tarlatamab discontinuation was advised if an initial grade 3 nonfebrile neutropenia did not improve to grade 1 or lower within 3 weeks or if an initial grade 4 nonfebrile neutropenia lasted for >7 days or recurred at a lower dose level. 

An alanine aminotransferase (ALT) increase was observed in 15 patients (11.3%), and two patients (1.5%) experienced a grade 3 event. The median time to onset of ALT increase from the first tarlatamab dose was 29 days (IQR, 7–113 days). For the 14 patients (10.5%) who had increased aspartate aminotransferase (AST) levels, the median time to onset was 51 days (IQR, 3–196 days). One patient had elevated aminotransferase and total bilirubin greater than two times the upper limit of normal and alkaline phosphatase less than two 2 times the upper limit of normal. Elevated blood bilirubin was observed in four patients (3%). No patient reported tarlatamab discontinuation because of increased ALT or AST levels. The changes in liver enzyme and bilirubin levels were generally transient, with no evidence suggesting extensive hepatocellular damage. Documenting baseline levels of liver enzymes and bilirubin before starting tarlatamab and monitoring before each dose of tarlatamab and as clinically indicated was performed in the DeLLphi‐301 trial. 

Other AEs reported in DeLLphi‐301 included decreased appetite, fatigue, anemia, and infections. Decreased appetite and fatigue are AEs that, if not appropriately monitored and managed, can negatively affect long‐term patient experience. In DeLLphi‐301, decreased appetite was reported in 48 of 133 patients (36%), and fatigue was reported in 32 of 133 patients (24%). Standard nonpharmacologic approaches, such as encouraging patients to undertake an optimal level of activity under the guidance of a health care provider, massage therapy, acupuncture, psychosocial interventions, nutrition consultations, and pharmacologic interventions, have been suggested for the management of fatigue in patients undergoing cancer treatment. Anemia was observed in 40 patients (30%), with a median time to onset of 13.0 days (range, 1–275 days) from the first tarlatamab dose. (Figure ). Among 57 patients with infections, the median time to onset was 37.0 days (range, 2–436 days). Grade ≥3 treatment‐emergent infections, including opportunistic infections, occurred in 17 of 133 patients (13%). The most frequent grade ≥3 treatment‐emergent infections were pneumonia ( n = 6), respiratory tract infection ( n = 3), device‐related infection, and pneumonia aspiration ( n = 2 each). Infections were managed using relevant institution‐specific protocols. For all infections, the prescribing information recommends withholding tarlatamab until resolution or, in the case of a grade 3 infection (graded according to Common Terminology Criteria for Adverse Events, version 5.0 guidelines ), withholding tarlatamab until infection improved to grade 1 or lower. Permanent discontinuation of tarlatamab was recommended in the case of a grade 4 infection. 

Early identification of the signs and symptoms of AEs and an awareness of management practices may help health care providers optimize care for patients who are receiving tarlatamab. Thus patients in the DeLLphi‐301 trial were monitored in a health care facility for 24–48 hours after the first two doses of tarlatamab. Investigators also took into consideration the ability to rapidly transfer patients to an intensive care unit to manage higher grade CRS or ICANS events. After hospital discharge, patients were to be accompanied by a caregiver and remain within 1 hour of an appropriate health care setting for a total of 72 hours postinfusion after the first two tarlatamab doses. Other considerations identified by investigators that can aid in optimizing the management of CRS and ICANS are listed in Table . Health care providers educated patients and caregivers on recognizing the signs and symptoms of CRS and ICANS. They were taught to recognize CRS symptoms, such as fever, difficulty breathing or unusual shortness of breath, headache, chest pain, palpitations, persistent nausea or vomiting, chills, and/or myalgia, and were advised on the appropriate administration of acetaminophen. Patients and caregivers were also instructed on monitoring changes in vital signs (body temperature [≥38°C], blood pressure, oxygen saturation, and heart rate) for the early identification of AEs. When a patient living in a rural setting developed symptoms suggestive of CRS, the patient and caregiver were instructed to treat with dexamethasone and visit the emergency room for further help. Patients and caregivers were also taught to recognize neurologic symptoms that could be manifestations of ICANS, such as headache, dysgeusia, dizziness, insomnia, muscular weakness, ataxia, amnesia, confusion, disorientation, and lethargy. They were instructed to call or see their treating health care provider right away or go to the emergency room if they experienced any neurologic symptoms at any time during their treatment with tarlatamab. Patients were also advised to refrain from driving, operating heavy or potentially dangerous machinery, and engaging in hazardous occupations or activities until their neurologic symptoms resolved. Patient or caregiver diaries with a descriptive record of symptoms, timing, and duration of AEs can assist health care providers with the management of AEs (Table ). In addition, at one site, patients and caregivers were provided wallet cards with key contact information and asked to show the wallet card to health care providers. 

To date, the experience with chimeric antigen receptor T‐cell therapies in hematologic malignancies has driven the management of CRS and ICANS. However, it is important to distinguish the safety profile of tarlatamab. In the DeLLphi‐301 trial, CRS and ICANS were generally low‐grade and manageable with standard supportive care that included acetaminophen, intravenous hydration, and/or glucocorticoids. CRS‐associated fever usually occurred within hours of tarlatamab administration and was sometimes the only symptom before it resolved. Progression to higher‐grade CRS generally took hours and, in most instances, was conservatively managed. ICANS occurred with a relatively low incidence, was low‐grade, and was typically managed with corticosteroids. Although ICANS occurred more frequently in patients who had treated, stable brain metastases in the DeLLphi‐301 phase 2 trial, this correlation was not observed in the DeLLphi‐300 phase 1 trial. , Additional AEs experienced by patients treated with tarlatamab include cytopenias, liver enzyme elevations and dysgeusia, which typically can be managed with standard of care (Figure ). 

Clinical trial experience indicates that tarlatamab has a manageable safety profile with a low discontinuation rate (3%) because of treatment‐related AEs. Tarlatamab‐associated AEs, including immune‐related AEs like CRS and ICANS, were primarily grade 1 or 2 in severity, mostly occurred early during treatment (cycle 1), and generally could be managed with standard supportive care. Monitoring, detection, and appropriate management of AEs like CRS and ICANS will remain important for maintaining the continuity of care. Knowledge of other AEs, such as neutropenia, transient liver enzyme elevations, and dysgeusia, is also important to consider, especially during the long‐term treatment of patients on tarlatamab. Continuous patient education by nurses and pharmacists may help with symptom monitoring and management and optimize long‐term patient treatment experience. 

Jacob M. Sands : Conceptualization; writing—review & editing; investigation. Stéphane Champiat : Conceptualization; investigation; writing—review & editing. Horst‐Dieter Hummel : Conceptualization; investigation; writing—review & editing. Kelly G. Paulson : Conceptualization; investigation; writing—review & editing. Hossein Borghaei : Conceptualization; investigation; writing—review & editing. Jean Bustamante Alvarez : Conceptualization; investigation; writing—review & editing. David P. Carbone : Conceptualization; investigation; writing—review & editing. Jennifer W. Carlisle : Conceptualization; investigation; writing—review & editing. Noura J. Choudhury : Conceptualization; investigation; writing—review & editing. Jeffrey M. Clarke : Conceptualization; investigation; writing—review & editing. Shirish M. Gadgeel : Conceptualization; investigation; writing—review & editing. Hiroki Izumi : Conceptualization; investigation; writing—review & editing. Alejandro Navarro : Conceptualization; investigation; writing—review & editing. Sally C. M. Lau : Conceptualization; investigation; writing—review & editing. Philip E. Lammers : Conceptualization; investigation; writing—review & editing. Shuang Huang : Conceptualization; methodology; validation; writing—review & editing; formal analysis; data curation. Ali Hamidi : Conceptualization; writing—review & editing; formal analysis; validation; methodology; data curation. Sujoy Mukherjee : Conceptualization; methodology; validation; writing—review & editing; formal analysis; data curation. Taofeek K. Owonikoko : Conceptualization; investigation; writing—review & editing. 

Jacob M. Sands reports research funding from Amgen and Harpoon; personal/consulting fees from Amgen Inc., AstraZeneca, Boehringer Ingelheim, AbbVie, Daiichi Sankyo/UCB Japan, Eli Lilly & Company; G1 Therapeutics, Gilead Sciences, Guardant Health, Jazz Pharmaceuticals Inc., Medtronic Inc., PharmaMar, and Sanofi; honoraria from Pfizer; and support for travel/accommodation and expenses from AstraZeneca outside the submitted work. Stéphane Champiat reports institutional research funding from AbbVie, AdaptImmune, Adura Biotech, Agios, Amgen, arGEN‐X BVBA, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Bayer, BB Biotech Ventures, BeiGene, BioAlliance Pharma, BioNTech, Blueprint Medicines, Boehringer Ingelheim, Bolt Biotherapeutics, Boston Pharmaceuticals, Bristol Myers Squibb, Celgene, Centessa Pharmaceuticals, Cephalon, Chugai Pharma, Clovis Oncology, Cullinan Oncology, Cytovation, Daiichi Sankyo, Debiopharm Group, Eisai, Eli Lilly & Company, Exelixis, FORMA Therapeutics, Genentech, Gilead Sciences, GlaxoSmithKline, Glenmark, H3 Biomedicine, Roche, ImCheck Therapeutics, Immunocore, Incyte, Innate Pharma, Janssen‐Cilag, Kura Oncology, Kyowa Hakko Krin, Loxo, Lytix Biopharma, MedImmune, Menarini, Merck KGaA, Merck Sharp & Dohme, Merrimack, Merus, Millennium, Molecular Partners, Nanobiotix, Nektar, Nerviano Medical Sciences, Novartis, Octimet, Oncoethix, OncoMed, Oncopeptides, Onyx, Orion, Oryzon Genomics, OSE Immunotherapeutics, Pfizer, PharmaMar, Philogen, Pierre Fabre, Plexxikon, Replimune, RigonTEC, Roche/Genentech, Sanofi/Aventis, Seagen, SERVIER, Sierra Oncology, Sotio, Syros Pharmaceuticals, Taiho Pharmaceutical, Tesaro, Tioma Therapeutics, Transgene, Turning Point Therapeutics, Vericyte, Wyeth, Y's Therapeutics, and Zencor; other institutional support from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly & Company, GlaxoSmithKline, Johnson & Johnson, Medimmune, Merck, NH TherAguix, Pfizer, and Roche; honoraria from Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai Europe, Fresenius Kabi, Genmab, Janssen Pharmaceuticals, Merck KGaA, Merck Serono, Merck Sharp & Dohme, Novartis, Roche, SERVIER, and Takeda Oncology; personal/consulting or advisory fees from Alderaan Biotechnology, Amgen, AstraZeneca, Avacta Life Sciences, Bayer, BioNTech SE, Celanese, Computen, Domain Therapeutics, Ellipses Pharma, Genmab, Immunicom, Mariana Oncology, Mima Health, Nanobiotix, NextCure, Oncovita, Pierre Fabre, Seagen, Takeda Oncology, Tatum Bioscience, Tollys, and UltraHuman8; patents, royalties, and other intellectual property for patent number WO2010039223A2 (T‐cell immunogens derived from antiviral proteins and methods of using same); support for travel/accommodations and expenses from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck, OSE Immunotherapeutics, Roche, and Sotio; and owns stock options in Avacta Life Sciences outside the submitted work. Horst‐Dieter Hummel reports institutional support for professional activities from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Johnson & Johnson/Janssen, Merck, and Revolution Medicines; personal/consulting or advisory fees from Amgen and Boehringer Ingelheim; honoraria from Amgen; and support for travel/accommodations and expenses from Amgen and Boehringer Ingelheim outside the submitted work. Hossein Borghaei reports grants/contracts from Amgen; institutional research funding from Amgen, Bristol Myers Squibb, and Eli Lilly & Company; personal/consulting or advisory fees from AbbVie, Amgen, AstraZeneca, Bayer, BeiGene USA Inc., BerGenBio, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo/UCB Japan, Eli Lilly & Company, EMD Serono, Genentech, Genmab, Grid Therapeutics, Guardant Health, IO Biotech, ITeos Therapeutics, IO Biotech, Janssen Oncology, Jazz Pharmaceuticals, Merck KGaA, Merck Sharp & Dohme, Mirati Therapeutics, Natera, Novartis, Novocure, Oncocyte, Pfizer, PharmaMar, Puma Biotechnology, RAPT Therapeutics, Regeneron Pharmaceuticals, Rgenix, Sonnet, and Takeda Oncology; service on a Data and Safety Monitoring Board for Incyte Corporation, Novartis, SpringWorks, and Takeda Oncology; support for travel/accommodations and expenses from Amgen, Bristol Myers Squibb, Celgene, Clovis Oncology, Eli Lilly & Company, EMD Serono, Genentech, Merck, Mirati Therapeutics; stock and other ownership interests in Nucleai, Rgenix, and Sonnet; and stock options in Inspirina and Nucleai outside the submitted work. David P. Carbone reports honoraria from AstraZeneca and Bristol Myers Squibb‐Ono Pharmaceutical; and personal/consulting or advisory fees from AbbVie, Amgen, Arcus Biosciences, AstraZeneca, Arcus Biosciences, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Bristol Myers Squibb Israel, Curio Science, Daiichi Sankyo, Dava Oncology LP, Eli Lilly & Company, EMD Serono, F. Hoffmann‐LaRoche, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline LLC, Intellisphere, InThought, Iovance Biotherapeutics, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Johnson & Johnson Health Care Systems Inc., Johnson & Johnson/Janssen, Lumanity Commercial BioConsulting, Merck & Company Inc., Merck KGgA, Mirati Therapeutics, MSD Oncology, Novartis, Novocure, OncoHost, OncoLive/MJH Life Sciences, Pfizer, PPD, Regeneron Pharmaceuticals, Roche/Genentech, and Sanofi outside the submitted work. Jennifer W. Carlisle reports grants/contracts from Daiichi Sankyo, Genentech, and PAREXEL International; institutional research funding from Amgen, AstraZeneca, Hutchmed, and Parexel; and personal/consulting or advisory fees from Amgen, AstraZeneca, Catalyst Pharmaceuticals Inc., Novocure, and Sanofi outside the submitted work. Noura J. Choudhury reports institutional research funding from AbbVie, Amgen, Harpoon Therapeutics, Merck, MonteRosa Therapeutics, and Roche/Genentech; personal/consulting or advisory fees from AbbVie, Eli Lilly & Company, Harpoon Therapeutics, Sanofi, and SG1 Therapeutics; and royalties from Wolters Kluwer outside the submitted work. Jeffrey M. Clarke reports grants/contracts from Abel Zeta, AdaptImmune, Amgen, AstraZeneca, BioThera, Bristol Myers Squibb, Grid Therapeutics, Moderna, Pfizer, Spectrum Pharmaceuticals, and Zai; personal/consulting or advisory fees from AbbVie, Amgen, AstraZeneca, Black Diamond, Bristol Myers Squibb, CDR Life, Coherus BioSciences, Corbus, DSI, G1 Therapeutics, Merck, Moderna, Sanofi, and Spectrum Pharmaceuticals; service on a Data and Safety Monitoring Board for BioThera and G1 Therapeutics; and support for other professional activities from Amgen outside the submitted work. Shirish M. Gadgeel reports institutional research funding from Amgen, Astellas Pharma, AstraZeneca, BioMed Valley Discoveries, Blueprint Medicines, Calithera Biosciences, Genentech/Roche, Daiichi Sankyo, Debiopharm Group, Dragonfly Therapeutics, eFFECTOR Therapeutics, Elevation Oncology, Erasca Inc., Helsinn Therapeutics, I‐Mab, Incyte, InventisBio, Janssen Oncology, Merck, Mirati Therapeutics, Nektar, Numab, Pfizer, Regeneron, Turning Point Therapeutics, Verastem, and Ymabs Therapeutics; personal/consulting or advisory fees from AbbVie, Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly & Company, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, I‐MAB, Janssen Oncology, Merck, Mirati Therapeutics, Novartis, Nuvation Bio, Pfizer, Regeneron, and Takeda Oncology; honoraria from Merck; support for other professional activities from AstraZeneca; and travel support from Merck and Mirati Therapeutics outside the submitted work. Hiroki Izumi reports grants/contracts from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, and Takeda; institutional research funding from AbbVie, Amgen, ArriVent Biopharma, AstraZeneca, Eisai/MSD, Ono Pharmaceutical, and Takeda; and honoraria from Bristol Myers Squibb Japan, Chugai/Roche, Eli Lilly & Company, Merck, Merck Sharp & Dohme, Ono Pharmaceutical, and Takeda outside the submitted work. Alejandro Navarro reports personal/consulting or advisory fees from Adium Pharma, Amgen, Boehringer Ingelheim, Bristol Myers Squibb Foundation, Eczacibasi, Genomics, Oryzon, Pfizer, and Takeda; service on a Data and Safety Monitoring Board for Hengenix Biotech Inc. and MedSIR; speakers bureau fees from AstraZeneca Spain and Roche; support for other professional activities from Merck Sharp & Dohme; expert witness testimony for AstraZeneca, Boehringer Ingelheim Espana S.A., Bristol Myers Squibb, F. Hoffmann‐La Roche, Pfizer, and Takeda; and travel support from F. Hoffmann‐La Roche outside the submitted work. Philip E. Lammers reports personal/consulting or advisory fees from Amgen, AstraZeneca, Daiichi Sankyo, Merck, Pfizer, Roche/Genentech, Sanofi, and Teva outside the submitted work. Shuang Huang is an employee of Amgen and owns stock in the company. Ali Hamidi is an employee of Amgen and owns stock and stock options in the company. Sujoy Mukherjee is an employee of Amgen and owns stock in the company. Taofeek K. Owonikoko reports grants/contracts from Eli Lilly & Company; institutional research funding from AbbVie, Amgen, AstraZeneca/MedImmune, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Corvus Pharmaceuticals, G1 Therapeutics, GlaxoSmithKline, Incyte, Loxo/Lilly, Merck, Meryx Pharmaceuticals, Novartis, Oncorus, Pfizer, Regeneron, and Roche/Genentech; personal/consulting or advisory fees from Amgen, AbbVie, AstraZeneca, Bayer, BeiGene, BerGEnBio, Boehringer Ingelheim, Bristol Myers Squibb, Cambium Oncology, Celgene, Coherus Biosciences, Daiichi Sankyo, Eisai, Eli Lilly & Company, EMD Serono, Exelixis, G1 Therapeutics, Heat Biologics, Ipsen, Janssen Biotech Inc., Jazz Pharmaceuticals Inc., MedImmune, Merck, Meryx Pharmaceuticals, Novartis, Oncocyte, PharmaMar, Puma Biotechnology, Roche/Genentech, Takeda, Triptych Health Partners, and Xcovery; service on a Data and Safety Monitoring Board for Genentech; service on an End Point Review Committee for Takeda Oncology; support for other professional activities from EMD Serono, Novartis, and Roche/Genentech; an uncompensated relationship with Reflexion Medical; has patents, royalties, and/or other intellectual property related to DR4 Modulation and its Implications in EGFR‐Target Cancer Therapy Ref: 18089 provisional (collaborative search pilot; US Patent Application No. 62/670,210; June 26, 2018; co‐inventor; institutional), Overcoming Acquired Resistance to Chemotherapy Treatments Through Suppression of STAT3 (institutional), Selective Chemotherapy Treatments and Diagnostic Methods Related Thereto (institutional), and Soluble FAS Ligand as a Biomarker of Recurrence in Thyroid Cancer (provisional; patent no. 61/727,519; inventor; institutional); support for travel/accommodations and expenses from AstraZeneca and Janssen; and owns stock and has other ownership interests in Cambium Medical Technologies, Coherus Biosciences, GenCart, and Taobob LLC outside the submitted work. The remaining authors disclosed no conflicts of interest. 

Supplementary Material 

