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Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers. Despite high rates of response to first-line chemotherapy and radiotherapy, patients with extensive-stage disease eventually relapse, and very few patients survive more than 5 years from diagnosis. Treatment options for recurrent or refractory disease are limited, and the treatments that do exist are associated with significant treatment-related toxicities. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed in SCLC and other neuroendocrine tumors but minimally expressed in normal tissues. It is therefore being explored as a potential therapeutic target in SCLC. Here, we review the preclinical and clinical evidence for targeting DLL3 in SCLC and discuss several DLL3-specific therapies being developed for the treatment of SCLC: the antibody-drug conjugate rovalpituzumab tesirine, the bispecific T cell engager immuno-oncology therapy AMG 757, and the chimeric antigen receptor T cell therapy AMG 119.

8032 Background: Teclistamab (tec; JNJ-64007957) is a BCMA × CD3 T-cell redirecting bispecific antibody under investigation in patients (pts) with RRMM. Daratumumab (dara) is a CD38 mAb with direct on-tumor and immunomodulatory actions. Initial clinical data from the phase 1b multicohort TRIMM-2 study support the combination of tec + dara for the treatment of RRMM, with tolerable safety, no overlapping toxicities, and promising efficacy. We present updated results with additional pts and longer follow-up. Methods: Eligible MM pts aged ≥18 y had received ≥3 prior lines of therapy (LOT; including a proteosome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double-refractory to a PI and IMiD. Pts treated with anti-CD38 therapy ≤90 d prior were excluded. Pts received dara SC 1800 mg per approved schedule and tec SC 1.5–3 mg/kg QW or Q2W. Primary objectives were to identify the recommended phase 2 dose of tec for combination therapy and evaluate safety of the combination. Responses were assessed by IMWG criteria. AEs were graded per CTCAE v5.0; cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. Results: At data cutoff (Jan 13, 2022; safety population: N=46), median follow-up was 7.2 mo (range 0.1–16.6; median age 67 y [range 50–79]; 52% female). Pts received a median of 6 prior LOT (range 2–17; 74% triple-class exposed; 63% penta-drug exposed; 15% anti-BCMA exposed). 91% of pts had ≥1 AE (grade 3/4 78%), most commonly CRS (61%; all grade 1/2; median time to onset 2 d; median duration 2 d), neutropenia (54%; grade 3/4 50%), anemia (46%; grade 3/4 28%), thrombocytopenia (33%; grade 3/4 28%), and diarrhea (33%; grade 3/4 2%). Infections occurred in 29 pts (63%; grade 3/4 28%). One pt had grade 1 ICANS that fully resolved. Among 37 response-evaluable pts, ORR was 78% (29/37); 27 pts (73%) had very good partial response (VGPR) or better (Table). Median time to first response across dosing cohorts was 1.0 mo (range 0.9–2.8); median duration of response was not reached. Upregulation of CD38+/CD8+ T cells and proinflammatory cytokines was observed with tec + dara, supporting potential synergy of the combination in pts with prior anti-CD38 exposure. Updated results will be presented. Conclusions: Tec + dara provides a novel immunotherapy approach for the treatment of RRMM that may yield improved clinical efficacy in heavily pretreated pts. Clinical trial information: NCT04108195. [Table: see text]

Background Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed in small cell lung cancer (SCLC) and minimally expressed in normal tissues.1 AMG 757, a half-life extended BiTE® immune therapy, binds to DLL3 on tumor cells and CD3 on T cells, resulting in T cell-dependent killing of tumor cells. We report initial safety and efficacy from the ongoing phase 1 study of AMG 757 in patients with SCLC. Methods AMG 757 was administered intravenously every two weeks (with/without step dose) at doses of 0.003–3.0 mg. Eligible patients had SCLC that progressed or recurred following ≥1 platinum-based regimen. Antitumor activity was assessed using modified RECIST 1.1. The study was approved by the Ethics Board at participating institutions. Results As of 1 June 2020, safety and efficacy data are available for 31 patients enrolled at the first seven dose levels (DL) with median age, 63 (44–74) years; ECOG PS: 0–1, n=30 (96.8%); median prior lines, 2.0 (1–6); and previous PD-1/PD-L1 treatment: n=12 (38.7%). Median treatment duration was 6.1 (0.1–59.4) weeks. Treatment-emergent adverse events (AEs) were reported for 30 (96.8%) patients. AMG 757-related AEs occurred in 25 (80.6%) patients, including 5 (16.1%) that were grade ≥3 and one (3.2%) grade 5 (pneumonitis in DL5 [0.3 mg]). Three AEs (dyspnea, pneumonitis, fatigue) led to treatment discontinuation. The most common AE was cytokine release syndrome (CRS), which was reported in 11 (35.5%) patients. CRS AEs were grade 1–2, consisted mainly of fever with/without hypotension, and occurred mostly within 24 hours of the first or second dose of AMG 757. CRS events were reversible, did not lead to treatment interruption or discontinuation, and were managed with supportive care, corticosteroids, and/or anti-IL 6 therapy. The MTD for AMG 757 has not yet been reached. AMG 757 exhibited dose proportional increase in exposures. Response to AMG 757 is shown (figure 1). Confirmed partial response was reported in 5 (16.1%) patients (1/12 [8.3%] in DL5, 1/8 [12.5%] in DL6, 3/7 [42.9%] in DL7), and stable disease in 8 (25.8%) of all treated patients. Most responses occurred after 8 weeks on treatment. All responders remain on treatment with duration of response ranging from 2.0+ to 7.4 months+. Conclusions AMG 757 administered at a dose of up to 3 mg every two weeks has an acceptable safety profile and shows anti-tumor activity in patients with relapsed/refractory SCLC. Further dose escalation is ongoing. Trial Registration NCT03319940 Ethics Approval The study was approved by the Ethics Board at participating institutions. Consent N/A Reference Leonetti A, Facchinetti F, Minari R, Cortellini A, Rolfo CD, Giovannetti E, Tiseo M. Cell Oncol (Dordr). 2019;42:261–273.

BackgroundTo determine the safety and efficacy of the anti-colony-stimulating factor 1 receptor (anti-CSF1R) monoclonal antibody AMG 820 in combination with pembrolizumab in patients with select solid tumors.Patients and methodsPatients had advanced, refractory mismatch repair-proficient colorectal cancer, pancreatic cancer, or non-small cell lung cancer (NSCLC) with low (ResultsOverall, 116 patients received ≥1 dose of AMG 820 plus pembrolizumab (18 at 1400 mg AMG 820; 98 at 1100 mg AMG 820). Most patients (64%) were male; the median age was 64 (range 30–86) years. Seven patients had DLTs (1 at 1400 mg AMG 820; 6 at 1100 mg AMG 820). Almost all patients (99.1%) had AEs, 87.9% with grade ≥3 AEs. The most common AEs were increased aspartate aminotransferase (59.5%), fatigue (48.3%), periorbital/face edema (48.3%), and rash/maculopapular rash (37.1%). The best response was immune-related partial response in 3 patients (3%; duration of response 9.2, 10.0, 12.5 months) and immune-related stable disease in 39 patients (34%). None of the completed phase II cohorts met the predefined threshold for efficacy. Post-treatment there was accumulation of serum colony-stimulating factor 1 (CSF1) and interleukin-34, reduction in CSF1-dependent CD16-expressing monocytes, and increased PD-L1 expression and CD4 and CD8 cell numbers in tumor biopsies.ConclusionsThe recommended combination dose of 1100 mg AMG 820 plus 200 mg pembrolizumab had an acceptable safety profile. Although pharmacodynamic effects were observed, antitumor activity was insufficient for further evaluation of this combination in selected patient populations.Trial registration numberNCT02713529

Purpose Patients with organ dysfunction, prior or concurrent malignancies, and comorbidities are often excluded from clinical trials. Excluding patients on the basis of these factors results in clinical trial participants who are healthier and younger than the overall population of patients with cancer. Methods ASCO and Friends of Cancer Research established a multidisciplinary working group that included experts in trial design and conduct to examine how eligibility criteria could be more inclusive. The group analyzed current eligibility criteria; conducted original data analysis; considered safety concerns, potential benefits, research, and potential hurdles of this approach through discussion; and reached consensus on recommendations regarding updated eligibility criteria that prioritize inclusiveness without compromising patient safety. Results If renal toxicity and clearance are not of direct treatment-related concern, then patients with lower creatinine clearance values of > 30 mL/min should be included in trials. Inclusion of patients with mild to moderate hepatic dysfunction may be possible when the totality of the available nonclinical and clinical data indicates that inclusion is safe. Ejection fraction values should be used with investigator assessment of a patient’s risk for heart failure to determine eligibility. Patients with laboratory parameters out of normal range as a result of hematologic disease should be included in trials. Measures of patient functional status should be included in trials to better assess fit versus frail patients. Conclusion Expanding inclusion of these patients will increase the number and diversity of patients in clinical trials and result in a more appropriate population of patients.

TPS9080 Background: SCLC is an aggressive neuroendocrine tumor with poor prognosis and few treatment options. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed on the surface of most SCLC tumors but minimally expressed in normal tissues. As such, DLL3 may be a promising therapeutic target. AMG 757 is an HLE BiTE immune therapy designed to redirect cytotoxic T cells to cancer cells by binding to DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. In addition to its direct antitumor effect, BiTE immune therapy can inflame the tumor microenvironment. Combining AMG 757 with a PD-1 pathway inhibitor may lead to increased antitumor activity by enabling sustained T cell-dependent killing of tumor cells. Methods: NCT03319940 is an open-label, ascending, multiple-dose, phase 1 study evaluating AMG 757 as monotherapy; the protocol was recently amended to also evaluate AMG 757 in combination with pembrolizumab. The study will include a dose exploration (monotherapy and combination) followed by a dose expansion (monotherapy). Key eligibility criteria: adult patients with relapsed/refractory SCLC whose disease progressed or recurred after at least 1 platinum-based chemotherapy regimen, ECOG performance status 0–2, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. Primary objectives are to evaluate safety/tolerability and determine the maximum tolerated dose or recommended phase 2 dose of AMG 757 as monotherapy and in combination with pembrolizumab. Secondary objectives are to characterize pharmacokinetics and evaluate preliminary antitumor activity; exploratory objectives are to assess immunogenicity and changes in biomarkers in blood and tumor tissue. In the dose exploration phase, dose escalation/de-escalation decisions will be guided by a Bayesian logistic regression model; backfill enrollment at dose levels deemed safe and tolerable will be allowed. The study is open and recruiting patients. Clinical trial information: NCT03319940.

TPS8576 Background: SCLC is an aggressive neuroendocrine tumor, with initial sensitivity to chemotherapy and radiotherapy often followed by chemoresistant disease progression. Notch signaling is a key regulator of neuroendocrine differentiation in SCLC, and delta-like ligand 3 (DLL3) is an inhibitory ligand of Notch receptors. DLL3 is expressed in most SCLC tumors but minimally expressed in normal tissues, suggesting that it may be a promising target for cancer immunotherapy. AMG 119 is an adoptive cellular therapy that consists of a patient’s autologous T cells that have been genetically modified ex vivo to express a transmembrane CAR that targets DLL3 and redirects cytotoxic T cell specificity to DLL3-positive cells. AMG 119 CAR T cells show potent killing of SCLC cells expressing DLL3 in vitro and inhibit tumor growth in an SCLC xenograft model in vivo. Methods: This phase 1 study will evaluate the safety and tolerability of AMG 119 administered as a single infusion in adult patients with relapsed/refractory SCLC who have progressed after at least 1 platinum-based chemotherapy regimen. The primary objectives are to evaluate safety and tolerability and determine the maximum tolerated cell dose (MTCD) or recommended phase 2 cell dose (RP2CD). Secondary objectives are to evaluate preliminary evidence of antitumor activity, expansion and persistence of AMG 119, and trafficking of AMG 119 to the tumor in post-treatment biopsy. Key inclusion criteria include histologically confirmed SCLC with radiographically documented disease progression or recurrence after at least 1 platinum-based regimen, ECOG performance status 0–1, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. In the cell dose exploration phase, 3–4 patients will receive a single IV infusion of AMG 119 at each cell dose. Cell dose escalation/de-escalation decisions will be guided by a modified toxicity probability interval design. The dose expansion phase will seek to confirm the MTCD or RP2CD and obtain further safety and efficacy data. Clinical trial information: NCT03392064.

2544 Background: In new drug/biologics applications, safety data provided to FDA include serious adverse events (SAEs), defined as adverse events (AEs) resulting in death, life-threatening AE, inpatient hospitalization or prolongation of hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or congenital anomaly/birth defect. One limitation of the SAE definition is that hospitalization practices differ across localities and among medical practitioners. Therefore, a safety signal may not be adequately reflected when analyzing SAEs. We hypothesize that evaluating CTCAE Grade 3 (severe) and Grade 4 (life-threatening) AEs, independent of whether or not these were classified as serious, provides a more complete assessment of patient safety. Methods: We reviewed SAEs from all nine registrational trials for new molecular entities approved for the treatment of cancer by the FDA in 2014. Results: A total of 25,548 AEs were reported in 1,781 patients treated with an investigational agent. There were 2,943 Grade 3-4 AEs and 912 Grade 3-4 SAEs. Information regarding hospitalization was available in 62% of Grade 3-4 AEs. Fifty-five percent of Grade 3-4 SAEs vs. 5.5% of Grade 3-4 non-serious AEs resulted in hospitalization. Several clinically serious Grade 3-4 AEs, including sepsis and respiratory failure, were not classified as SAE. Conclusions: There is significant overlap in most common Grade 3-4 AEs and most common Grade 3-4 SAEs. Most AEs that are clinically serious were appropriately classified as SAE. However, some clinically serious AEs and some AEs resulting in hospitalization were not classified as SAE. With the exception of information regarding hospitalization, characterization of the reason why certain AEs were classified as SAEs was not possible. In this pooled analysis, data from the analysis of AEs by severity was more informative than the analyses by SAEs. [Table: see text]

TPS8577 Background: SCLC is an aggressive neuroendocrine tumor; response to initial chemotherapy and radiotherapy is often followed by recurrence, rapid progression, and resistance to current therapies. Delta-like ligand 3 (DLL3) is an inhibitory ligand of Notch receptors that is expressed in most SCLC tumors but minimally expressed in normal tissues. DLL3 may therefore be a promising target for T cell–redirecting immunotherapy. AMG 757 is a half-life extended BiTE antibody construct that is designed to transiently connect DLL3-positive cells to CD3-positive T cells and induce T cell–mediated cell lysis and concomitant T cell proliferation. AMG 757 induces potent killing of SCLC cell lines in vitro and inhibits tumor growth in the SHP-77 human SCLC xenograft model in vivo. AMG 757 was well tolerated in a preclinical multi-dose toxicology study in cynomolgus monkeys, with no evidence of tissue damage at weekly doses up to 4.5 mg/kg. Methods: NCT03319940 is an open-label, ascending, multiple dose, phase 1 study evaluating AMG 757. The study will initially enroll adult patients with relapsed/refractory SCLC who have progressed after at least 1 platinum-based chemotherapy regimen. Additional inclusion criteria include ECOG performance status 0–2, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. Primary objectives are to evaluate safety and tolerability and to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Secondary objectives are to characterize pharmacokinetics (PK) and evaluate preliminary antitumor activity. In the dose exploration phase, patients will be monitored for dose-limiting toxicities during the first 28 days. A Bayesian logistic regression model will be used to inform dose escalation/de-escalation decisions. The dose expansion phase will confirm the MTD or RP2D and collect further safety and efficacy data. AMG 757 will be administered as a short-term intravenous infusion once every 2 weeks. Alternative dosing schedules may be explored based on emerging PK and safety data. Clinical trial information: NCT03319940.