T-Cell Engagers at ASCO 2026: MajesTEC-9 + Tarlatamab Long-Term + Solid-Tumor Wave

What to watch from May 29 – June 2 in Chicago — the CD3 T-cell engager class (bispecific antibodies that pull immune T cells onto cancer cells) saw major Phase 3 readouts in 2024–2025 and is now maturing from "last-line salvage" toward earlier-line standard of care.

Published May 24, 2026 • 9 min read • Pre-conference preview

What's Special About ASCO 2026 for TCEs

The 2024–2025 cycle was the "first wave" of T-cell engager approvals: tarlatamab (Imdelltra, May 2024) for ES-SCLC; elranatamab (Elrexfio) and the next-line BCMA-bispecific approvals in multiple myeloma; expanded lymphoma indications for epcoritamab and glofitamab. ASCO 2026 marks the transition from "this works as last-line" to "this works earlier" — with multiple Phase 3 confirmatory and earlier-line studies reading out.

The class still has two headwinds: cytokine release syndrome (CRS), which requires inpatient monitoring on the first 1–2 doses, and on-target off-tumor toxicity in solid tumors. ASCO 2026 will likely showcase solutions for both: subcutaneous formulations, hospital-at-home administration models, step-up dosing optimization, and a wave of "conditional" or "masked" TCEs that activate only inside tumors.

Small Cell Lung Cancer: The Tarlatamab Era Matures

Tarlatamab (Amgen's DLL3 × CD3 BiTE, brand Imdelltra) is now FDA full-approved for ES-SCLC after platinum chemotherapy (initial accelerated approval May 16, 2024 based on DeLLphi-301; full approval November 19, 2025 based on the Phase 3 DeLLphi-304 trial which showed a 40% reduction in risk of death vs standard-of-care chemotherapy — median OS 13.6 vs 8.3 months. Headline ASCO 2025 LBA, published concurrently in NEJM). Going into ASCO 2026, the open clinical questions are:

• 1L ES-SCLC induction + maintenance. The pivotal Phase 3 frontline trial is DeLLphi-312 — tarlatamab + durvalumab + carboplatin + etoposide (induction + maintenance) vs durvalumab + carboplatin + etoposide alone in untreated ES-SCLC. Phase 3 frontline data is maturing toward later 2026 / 2027 readouts, not the May 2026 program.
• 1L ES-SCLC maintenance. DeLLphi-305 — tarlatamab + durvalumab vs durvalumab alone as 1L maintenance after standard chemo-IO (EP + durvalumab) in ES-SCLC. The Phase 1b predecessor DeLLphi-303 reported median OS 25.3 months at 18.4-month follow-up (published Lancet Oncology 2025).
• Long-term follow-up — updated overall-survival data from DeLLphi-301 (the original pretreated-ES-SCLC Phase 2) and from the DeLLphi-304 cohort. Tail-of-the-curve data is the most clinically important number for patients deciding between tarlatamab and other post-platinum options.
• Subcutaneous tarlatamab and outpatient administration — Phase 1 readouts on SubQ formulations and hospital-at-home models could eliminate the inpatient monitoring requirement that has constrained adoption (currently FDA-mandated 22–24h observation for the first two doses).
• Combination platforms — DeLLphi-311 (tarlatamab + etakafusp alfa (AB248), a CD8+ T-cell-selective IL-2 from Asher Bio, in ES-SCLC; started September 2025) is now in dose-escalation and may have first-in-human safety updates.

The Big Question for ASCO 2026 isn't whether tarlatamab works — that's now established — it's where it sits in the SCLC treatment sequence: as 1L maintenance, as 2L after platinum, or as part of a multi-drug bispecific platform. Long-term OS curves and subcutaneous/outpatient data will shape that.

Multiple Myeloma: Teclistamab Monotherapy vs Standard 2L+ Care (MajesTEC-9)

Two myeloma cell-surface targets carry the CD3-bispecific story: BCMA (B-cell maturation antigen, found on plasma cells) targeted by teclistamab (Tecvayli), elranatamab (Elrexfio), and linvoseltamab; and GPRC5D (G protein-coupled receptor family C member 5D, also myeloma-restricted) targeted by talquetamab (Talvey). All four have FDA-approved indications in heavily pretreated multiple myeloma. The headline confirmed ASCO 2026 myeloma TCE abstract is:

The broader earlier-line program (MajesTEC-7 teclistamab + dara + len for transplant-ineligible newly-diagnosed MM; MagnetisMM-5 elranatamab monotherapy vs daratumumab + pomalidomide + dexamethasone in RRMM, which Pfizer reported as positive PFS in April 2026; MonumenTAL-3 talquetamab combinations; LINKER-MM-3 linvoseltamab) had its earlier readouts at ASH 2024 / ASCO 2024 / ASH 2025 and is in long-term follow-up. ASCO 2026 may bring updated PFS/OS data from those programs.

Patient takeaway: with MajesTEC-9 positive against PVd/Kd, teclistamab monotherapy is positioned to become an established 2L+ option in RRMM with payer support — an important practical move from the current label (which requires multiple prior lines and specific exposures). Side-effect profile remains the key tradeoff: bispecifics carry CRS, neurotoxicity, and significant infection risk from sustained immunoglobulin depletion.

GPRC5D vs BCMA — which first? Talquetamab (GPRC5D) and teclistamab/elranatamab (BCMA) have different toxicity profiles. GPRC5D causes characteristic taste/skin/nail toxicities; BCMA causes more infection and hypogammaglobulinemia. Emerging data on sequencing — whether one preserves response to the other on progression — will continue to mature.

Lymphoma: CD20 Bispecifics in Earlier-Line Combinations

Epcoritamab (Epkinly), glofitamab (Columvi), odronextamab (Ordspono), and mosunetuzumab (Lunsumio) are approved for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or both. The earlier-line combination Phase 3 trials in 1L DLBCL (epcoritamab + R-CHOP via EPCORE DLBCL-2, with EPCORE NHL-2 as the supporting Phase 1/2; odronextamab + CHOP via OLYMPIA-3) and the R/R DLBCL combinations (glofitamab + GemOx via STARGLO; SUNMO) had initial readouts at ASCO 2023–2025 and ASH 2024–2025. ASCO 2026 will most likely include long-term-follow-up updates and new subgroup analyses (high IPI risk, post-CAR-T setting, double-hit/triple-hit subsets):

The strategic question: will CD20 bispecifics replace CAR-T as second-line therapy for aggressive lymphoma? CAR-T (axi-cel, liso-cel, tisa-cel) is more effective but logistically heavy (manufacturing time, leukapheresis, single-center delivery). Bispecifics are off-the-shelf and outpatient-eligible after the first few doses. If the Phase 3 efficacy is comparable, bispecifics will become the broader-access option.

DLL3 Beyond SCLC: Tarlatamab in NEPC, NEC, Merkel Cell

Tarlatamab's target (DLL3, Delta-like 3) is expressed across multiple neuroendocrine cancers, not just SCLC. ASCO 2026 should bring Phase 2 readouts in:

• Neuroendocrine prostate cancer (NEPC) — DeLLpro-300 in metastatic prostate cancer with neuroendocrine features. NEPC is a lineage-defined subset of mCRPC that has poor response to AR-pathway agents (e.g., enzalutamab, abiraterone) and limited treatment options after platinum chemo failure.
• Extrapulmonary neuroendocrine carcinoma (EP-NEC) — digestive/pancreatic NEC, often pretreated with platinum-etoposide. Phase 2 vs standard chemotherapy in pretreated EP-NEC.
• Merkel cell carcinoma + other DLL3+ tumors — the RABBIT study (tarlatamab + concurrent radiation in DLL3-expressing tumors).
• DLL3+ glioma + astrocytic/oligodendroglial brain tumors — tarlatamab Phase 2 in adult and pediatric CNS tumors.

This is the test case for "is DLL3 a pan-tumor target?" If the response rates in EP-NEC and NEPC are meaningfully high, the FDA label is likely to expand beyond SCLC by 2027.

Solid Tumor TCEs: The Next Wave

Beyond DLL3, the solid-tumor CD3-TCE pipeline is uneven — some targets have active Phase 1/2 programs with early efficacy signals, while others (notably PSMA) have seen most lead programs discontinued for toxicity or modest activity. ASCO 2026 will bring updates on what's left and what's emerging:

Patient takeaway: if you have a solid tumor and are looking at trial options after standard therapy failure, biomarker testing on archival or fresh tumor biopsy is the gateway. Many of these TCEs require confirmation of target expression (CLDN18.2 IHC, GPC3 IHC, DLL3 IHC, KLK2 / PSMA PET-positive disease, etc.) before enrollment.

Tolerability and Administration: The Class Matures

The class's main limitations are operational: CRS in the first 1–2 doses requires inpatient monitoring; ongoing immunoglobulin depletion (especially with BCMA/CD20 bispecifics) raises infection risk; T-cell exhaustion can blunt response over time. ASCO 2026 will likely highlight:

• Subcutaneous formulations — subQ tarlatamab, subQ mosunetuzumab. SubQ delivery slows the cytokine release and reduces CRS severity. Could enable outpatient administration of step-up doses.
• Step-up dose optimization — finding the lowest-CRS dose schedule that still triggers efficacy. Some trials are testing 3-dose ramps vs the current 2-dose.
• Hospital-at-home administration — nurse-administered doses at the patient's residence with telemetry monitoring. Reduces the inpatient burden for patients without major comorbidities.
• Built-in co-stimulation (CD28 or CD2) — data from HLX3902, ZW209, EVOLVE104 showing sustained T-cell activity. AACR 2026 set the foundation; ASCO 2026 will bring earlier clinical efficacy data.
• IVIG prophylaxis schedules — for BCMA bispecifics, prophylactic IVIG can dramatically reduce serious infection rates. Schedule optimization data expected.

TCE vs CAR-T: The Patient Question

Patients in heme-onc clinics often hear about both T-cell engagers (TCEs) and CAR-T therapies and wonder which is better. The honest answer is "it depends":

• CAR-T: Higher response rates in multiple myeloma, DLBCL, and ALL. Single infusion (most products). But requires leukapheresis + 3–6 week manufacturing wait + single-center delivery + dedicated CRS/ICANS infrastructure.
• TCE bispecific: Off-the-shelf (no wait). Outpatient after step-up doses. Can be retreated indefinitely. Continuous dosing (vs single infusion). But ongoing toxicity from sustained immune activation; eventual T-cell exhaustion may blunt response over time.
• Practical reality: CAR-T is often used as a one-shot "high-stakes / high-effort" option for medically fit patients near a specialized center. TCEs are accessible to more patients, including those further from major centers or unable to wait for manufacturing. Comparative effectiveness data is still emerging.

For multiple myeloma: bispecifics are easier and reach more patients; CAR-T (cilta-cel, ide-cel) has higher response rates in pretreated disease. The ongoing question is whether earlier-line bispecific use changes the math.

For DLBCL/FL: bispecifics may be replacing CAR-T as the broader-access 2L option if Phase 3 data confirms comparable efficacy. CAR-T retains the "potential one-and-done" advantage.

What This Means for Patients Seeking Trials

• ES-SCLC patients: Tarlatamab is FDA-approved for pretreated ES-SCLC. Frontline + maintenance Phase 3 trials are recruiting — especially relevant if you haven't started chemo-IO yet.
• Multiple myeloma patients: Multiple bispecific combinations recruiting in 1L, 2L, and post-CAR-T settings. Bispecific selection (BCMA vs GPRC5D) and combination partner (dara/len/carfilzomib) varies by trial.
• R/R DLBCL or FL patients: If you've progressed on R-CHOP or are not eligible for CAR-T, bispecific monotherapy or combination trials are recruiting. 1L combination trials are also enrolling.
• NEPC, EP-NEC, MCC patients: DLL3-expressing tumors may qualify for tarlatamab Phase 2 trials. DLL3 IHC testing on biopsy is the typical entry criterion.
• Solid-tumor patients (gastric, ovarian, HCC, prostate): Several Phase 1/2 TCE trials are open. Biomarker testing (CLDN18.2, MUC16, GPC3, KLK2, STEAP1) on tumor biopsy is the gateway. Note: PSMA × CD3 programs have largely been discontinued for toxicity; current prostate-bispecific activity is in KLK2 (pasritamig) and STEAP1 (HLX3902, xaluritamig) targets.
• If you have CRS concerns: Several subcutaneous and hospital-at-home administration trials are open for tarlatamab and other TCEs — potentially reducing the inpatient monitoring burden.
• Coverage check: Tarlatamab is FDA-approved (covered by Medicare and most insurers for label indications). Trial enrollment generally has the sponsor cover the study drug; routine care is billed as standard insurance.

Find T-Cell Engager Trials for Your Cancer

Disease-Specific Trial Pages

Browse recruiting trials for cancers with active TCE development:

• SCLC Trials — tarlatamab Phase 3 frontline + maintenance + post-platinum + subcutaneous
• Multiple Myeloma Trials — teclistamab + dara + len; elranatamab + len; talquetamab combos; linvoseltamab
• Non-Hodgkin Lymphoma Trials — epcoritamab + R-CHOP; glofitamab + GemOx; odronextamab + R-CHP; mosunetuzumab combos
• Prostate Cancer Trials — tarlatamab in NEPC; KLK2 × CD3 (pasritamig / JNJ-78278343); STEAP1 × CD3 + CD28 (HLX3902; xaluritamig)
• Neuroendocrine Tumor Trials — tarlatamab in EP-NEC (digestive, pancreatic)
• Merkel Cell Carcinoma Trials — RABBIT study (tarlatamab + radiation in DLL3+ MCC and others)
• Gastric Cancer Trials — CLDN18.2 × CD3 bispecifics
• Ovarian Cancer Trials — MUC16 × CD3 (ubamatamab)
• HCC Trials — GPC3 × CD3 bispecifics
• All Tarlatamab Trials — 18 recruiting interventional studies across SCLC, NEC, NEPC, MCC, brain tumors
• Browse All Disease Trials

This article previews publicly anticipated abstracts and Phase 3 readouts for the ASCO 2026 Annual Meeting (May 29 – June 2, Chicago). Specific abstract IDs and final data values will be updated when the ASCO program is published (typically ~10 days before the meeting). This article is intended for educational purposes and does not constitute medical advice. Always discuss treatment options with your oncologist. See also: T-Cell Engagers at AACR 2026, ADC Therapies at AACR 2026, and Immunotherapy & Cell Therapy at AACR 2026.