SCLC Expert Addresses Key FAQs on ADCs, T-Cell Engagers, and First-Line Strategies

The small cell lung cancer (SCLC) landscape witnessed an influx of new data in 2026, with antibody-drug conjugates (ADCs) and T-cell engagers emerging as potential new standards of care in extensive-stage SCLC (ES-SCLC), including in the first-line setting.

At the 2026 ESMO Congress, data from the phase 3 DeLLphi-305 trial (NCT06211036) suggested a new standard of care for first-line maintenance in ES-SCLC: the T-cell engager tarlatamab-dlle (Imdelltra) plus durvalumab (Imfinzi).¹ At the interim analysis, the combination (n = 282) produced a median overall survival (OS) of 21.1 months (95% CI, 20.8-not estimable [NE]) vs 12.7 months (95% CI, 11.2-14.8) with durvalumab alone (n = 281; HR, 0.42; 95% CI, 0.32-0.54; P < .001). Tarlatamab plus durvalumab also improved progression-free survival (PFS), with a median PFS of 7.4 months (95% CI, 5.6-9.1) compared with 1.9 months (95% CI, 1.9-2.0) for durvalumab alone (HR, 0.34; 95% CI, 0.28-0.42; P < .001).

"[The] DeLLphi-305 outcomes support tarlatamab plus durvalumab as a new standard of care first-line maintenance therapy in ES-SCLC," said Jacob Sands, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, during his presentation of the data at the Presidential Symposium during the congress.

At the IASLC 2026 World Conference on Lung Cancer (WCLC), several abstracts offered new insights into the efficacy of B7-H3–directed ADCs and EGFR-directed tyrosine kinase inhibitors.

In the phase 3 TAISHAN-302 trial (NCT06612151), the B7-H3–directed ADC tambotatug pelitecan (tam-peli; YL201; n = 225) produced a median OS of 13.3 months (95% CI, 12.1-NE) compared with 9.4 months (95% CI, 7.7-10.5) with topotecan (n = 226) among patients whose SCLC had progressed after 1 prior line of platinum-based therapy (HR, 0.46; 95% CI, 0.35-0.62; P < .0001).² The median PFS was 7.4 months with tam-peli vs 2.8 months with topotecan (HR, 0.29; 95% CI, 0.23-0.37; P < .0001), and the confirmed overall response rates were 59.1% and 9.7%, respectively.

In the phase 3 ARTEMIS-008 trial (NCT06498479), treatment with risvutatug rezetecan (ris-rez; HS-20093/GSK5764227; n = 230), another B7-H3–directed ADC, led to a median OS of 18.5 months vs 10.3 months with topotecan (n = 231) in patients with SCLC whose disease progressed after first-line platinum-based therapy (HR, 0.46; 95% CI, 0.35-0.62; P < .0001).³ Per blinded independent central review, the median PFS was 7.2 months vs 3.0 months, respectively (HR, 0.33; 95% CI, 0.25-0.42).

However, the 2026 slate of positive, practice-changing data has raised prominent questions about treatment sequencing, regulatory decisions, and research priorities for 2027 and beyond.

SCLC expert Misty D. Shields, MD, PhD, tackled many of the most debated questions in the field, including the roles of ADCs and cellular therapy in relapsed disease, T-cell engager sequencing, first-line treatment selection, adjuvant therapy, molecular subtyping, and EGFR-mutant transformed SCLC.

Shields received and answered questions as part of an OncLive® Ask Me Anything session at the 2026 WCLC in Seoul, South Korea. Be sure to check out previous episodes featuring notable lung cancer experts, such as Balazs Halmos, MD, and stay tuned for Shields' episode on our YouTube channel, "OncLiveTV."

Shields is an assistant professor of clinical medicine in the Department of Medicine at Indiana University School of Medicine. She is also an adjunct assistant professor of medical and molecular genetics and an associate member of Experimental and Developmental Therapeutics at Indiana University Melvin and Bren Simon Comprehensive Cancer Center in Indianapolis.

Q: Which ADCs are showing the most promising results in ES-SCLC in 2026?

A: ADCs in [SCLC] are showing exciting outcomes. We see high response rates [and a] quick time to response, typically [at the] first scan, [with] meaningful and durable responses.

The treatments are impacted by myelosuppression, or low blood counts [of] red cells, white cells, [and] platelets, that might put patients at risk for infections or needing additional transfusions or support, as well as growth factors such as G-CSF. These ADCs may also have other toxicities, like gastrointestinal toxicities, nausea, vomiting, [and] diarrhea, that need additional support and mitigation.

We're seeing ADCs in the extensive-stage setting with [ifinatamab deruxtecan], a B7-H3 ADC that is under review, with a Prescription Drug User Fee Act date anticipated in October by the [FDA]. We have also seen sacituzumab govitecan [Trodelvy], a TROP2 ADC, showing great promise with a response rate of 42% in the second-line setting. We've seen [ABBV-706], a SEZ6 ADC, showing promising results, all of these agents having intracranial efficacy. We've also seen DLL3 ADCs showing great promise, even in patients who have had prior T-cell engagers targeting DLL3. It's hard to say which one is the best or most exciting one. I think they're all great, exciting, and showing incredible promise for our patients. Hopefully we will get these soon for regulatory approval here. We have also seen the data for [2] B7-H3 ADCs that have been under investigation [in] China only, both showing improvement over the standard-of-care topotecan in the second line, [with] improvement in PFS and OS.

Global access will be key, and this is demonstrating a new standard of care for relapsed/refractory [SCLC].

Q: Following data from the phase 3 DeLLphi-304 trial (NCT05740566) of tarlatamab-dlle, how should T-cell engagers and ADCs be sequenced in SCLC?

A: We've seen here at [WCLC] 2026 [2] B7-H3 ADCs demonstrating improvement over historical second-line topotecan. We also know from DeLLphi-304 that tarlatamab demonstrated significant improvement over the standard of care of topotecan, lurbinectedin [Zepzelca], or amrubicin for patients in Japan. It's unclear, [as] these agents are coming, how we will sequence them. This is the role of biomarkers. You can anticipate that the landscape is shifting with the first-line maintenance data being positive.

We also have [the phase 3] DeLLphi-312 [trial; NCT07005128], which is outstanding and first-line; we haven't seen that data yet. Hopefully we will see that soon at a future congress. That might mean that we're having patients on tarlatamab or T-cell engagers at diagnosis of [ES-SCLC]. We're seeing a shift in trying to understand where these T-cell engagers fall.

Is it at diagnosis? Is it at maintenance? Is it at second line? We don't want patients to have any attrition where they're not receiving therapies [in the] second line and beyond, so this is where supportive care is absolutely key to make sure patients stay on therapy and are living well with SCLC. In terms of the ADCs, it'll be hard to know where they will fall. We are also seeing those in the first-line setting, potentially replacing the chemotherapy that we have known for decades. Will this potentially [outperform] our known chemotherapy that has been our tried and true [option] for SCLC for 40 years? This is an ongoing study; we'll hopefully see that data soon.

This is also where biomarker discovery and biomarker implementation will be key to know which ADC patients should pursue, and [whether] the payload of a topoisomerase inhibitor [limits] that, where we may have only one shot on goal.

Q: In relapsed SCLC, which holds more promise: ADCs or CAR T-cell therapy?

A: ADCs are important. They are highly efficacious. They have great response rates. They work quickly, which could help some of our patients who might have a symptomatic crescendo of their [SCLC] and could potentially be hospitalized or have bad outcomes. [ADCs] have been effective for some of my patients where maybe a treatment stopped working, and they needed to have something that was effective to get them out of that bind.

[With] CAR T-cell therapy, we've seen many of them looking at DLL3 and other armored [CARs]. These are really exciting. The response rates are not quite where I'd like them to be just yet, but they do show initial toxicity and logistics, and may help us to learn more, just like [rovalpituzumab tesirine] did for DLL3. That knowledge helped us to inform the T-cell engager tarlatamab, which has now been so impactful and meaningful for patients worldwide. CAR T-cell therapy could mean a durable, meaningful, long-term impact for our patients with [SCLC]. That might be a really exciting avenue going forward; it just needs a little bit of tweaking to get there.

Q: What is your preferred first-line regimen for ES-SCLC after the phase 3 IMforte trial (NCT05091567), and how might DeLLphi-305 change practice?

A: First-line therapy for [ES-SCLC] is rapidly evolving. Historically, it was platinum/etoposide [Etopophos] until 2018 and 2019, with the implementation of anti–PD-L1 therapy with either atezolizumab [Tecentriq], with the phase 3 IMpower133 trial [NCT02763579] data, or durvalumab, with the phase 3 CASPIAN trial [NCT03043872] data. That was the standard of care until 2025, with the IMforte data looking at lurbinectedin in the maintenance setting with atezolizumab, importantly, permitting that there was no evidence of brain metastases at diagnosis or at restaging scans following chemoimmunotherapy.

We've also seen the recent exciting press release of DeLLphi-305; this may become our new standard of care. We know that the phase 1b DeLLphi-303 trial [NCT05361395] of tarlatamab with either anti–PD-L1 agent showed an impressive survival of 25 months and not reached. We anticipate that this will be a meaningful benefit over the historical standards of approximately 12 or 13 months with chemoimmunotherapy. Right now, for my patients, permitting no brain metastases and no progression on chemoimmunotherapy induction, I'm doing the IMforte regimen.

Q: What adjuvant therapy do you recommend after surgical resection of SCLC, and is there a role for immunotherapy?

A: When we're thinking about adjuvant therapy for [SCLC], we're thinking [of] the historic backbone of both platinum and etoposide. Historically, that platinum agent has always been cisplatin. But when we saw the data from the phase 3 ADRIATIC trial [NCT03703297] showing that there was equipoise between the carboplatin [Paraplatin] and cisplatin, [that] has helped me to change my practice, where I'm avoiding using cisplatin in most cases, given the additional hydration and chair time in our infusion centers [and] the risk for nephrotoxicity, as well as ototoxicity, [which] could be meaningful and in some cases severe or permanent. We also are avoiding cisplatin in practice due to the risk for electrolyte abnormalities, particularly magnesium.

In the adjuvant setting for SCLC, we're thinking of 4 cycles of platinum and etoposide, followed by guideline-based imaging at the appropriate intervals. Immunotherapy for adjuvant [therapy] is not yet there in terms of guideline-directed care. [An ongoing study] is looking at the role of immunotherapy in this setting, [so] stay tuned. But for now, we are doing 4 cycles of chemotherapy and close monitoring with scans, including brain MRIs, which is pivotal [to] make sure that there's no risk of recurrence for our patients with SCLC.

Q: Can patients currently learn their SCLC molecular subtype from pathology or genetic testing, and what is the phase 2 PRISM trial (NCT06769126) evaluating?

A: We are starting to see rollouts of neuroendocrine subtyping, meaning [ASCL1, NEUROD1, POU2F3, and] inflamed subtypes. There is a [SWOG] cooperative group study with [Anne Chiang, MD, PhD, and Carl Gay, MD, PhD,] investigating the neuroendocrine subtypes and if they can inform treatment decisions. This is an active, ongoing investigational study looking at the first-line maintenance setting, with tailoring based on the neuroendocrine subtype that is identified in the initial chemoimmunotherapy induction phase.

We haven't had enough information to say [whether] these biomarkers [are] actionable to tailor treatment. [The investigators] are doing a tremendous effort to look at several hundred patient samples, to look at subtyping in real time. While we don't have this yet available to us in our clinical practice, it is being studied. These are looking typically at what we call methylation, or the epigenetic profile of these transcription factors or subtypes.

Q: For patients with EGFR-mutant non–small cell lung cancer that transforms to SCLC, what role do T-cell engagers play, and what are next steps after platinum/etoposide?

A: There is quite a bit of controversy when we're thinking about the treatment of EGFR-transformed [SCLC]. Do you continue the EGFR-targeted therapy or not? Do you use immunotherapy or not? What do you do if that fails, which is commonly the case? Most patients who have EGFR-transformed [SCLC] are typically young, they typically have limited or no tobacco history, and they have aggressive disease. Following platinum/etoposide, which typically has a limited and transient benefit, what do we do next? Do we continue these therapies with EGFR targeting the non–small cell clone that is driven by that EGFR? What about pneumonitis and other risks of drug-drug interactions or potentially other toxicities that we don't want our patients to experience? Is there a role for T-cell engagers in this patient population?

We know that patients who have small cell transformation have a significant upregulation of DLL3. But we've seen from [2] case series that there has been minimal efficacy with the use of T-cell engagers like tarlatamab in this patient population. Is this a home run for our patients? I'm not quite sure. I also have a clinical trial that I have launched as an investigator-initiated study looking at lurbinectedin and osimertinib in transformed [SCLC], based on preclinical data to suggest there's synergy. This is in collaboration with a good friend and colleague of mine, [Triparna Sen, PhD,] at Ohio State. We're going to be investigating this both clinically and preclinically to understand the biomarkers of those who hopefully will respond, and, [for] those who do not, to understand why they didn't.

References

1. Sands J, Yoshida T, Ahn MJ, et al. Tarlatamab plus durvalumab vs durvalumab as first-line maintenance therapy following first-line durvalumab, platinum, and etoposide in extensive-stage small cell lung cancer: primary analysis of the phase 3 DeLLphi-305 trial. Paper presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA3
2. Zhang L, Zhao Y, Liu H, et al. Tam-peli, an anti-B7-H3 antibody-drug conjugate, versus topotecan in relapsed SCLC: a randomized, open-label, phase 3 study. Paper presented at: IASLC 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract PL02.03
3. Wang J, Wang L, Duan J, et al. Risvutatug rezetecan (a B7-H3-directed ADC) versus topotecan in relapsed SCLC: primary results of phase 3 ARTEMIS-008. Paper presented at: IASLC 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract PL02.04