Small cell lung cancer (SCLC) is a neuroendocrine lung cancer strongly linked to tobacco exposure. It accounts for about 15% of lung cancers, with roughly 150,000 new diagnoses worldwide each year. For decades, it has been one of thoracic oncology’s toughest problems: rapid tumor proliferation, aggressive biology, and late-stage diagnosis in most patients have limited meaningful treatment progress.
Even in limited-stage SCLC (LS-SCLC), surgery is feasible in fewer than 5% of cases, so most patients receive concurrent chemoradiotherapy as curative-intent treatment. In extensive-stage SCLC (ES-SCLC), platinum–etoposide has long been the first-line standard, yet overall survival has remained under 12 months. With limited new options, SCLC has been described as an “orphan disease” and a difficult landscape for drug development.
Before immunotherapy, notable advances in ES-SCLC were radiotherapy strategies and brain-directed prevention: consolidative thoracic radiotherapy for chemotherapy responders, plus prophylactic cranial irradiation (PCI) or MRI brain surveillance—important because more than 50% of patients ultimately develop intracranial metastases.
Key messages
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Molecular subtyping and immunotherapy have reshaped how researchers think about SCLC.
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DLL3-directed tarlatamab improved overall survival versus chemotherapy in second-line ES-SCLC, with distinctive immune toxicities to manage.
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B7-H3–directed ifinatamab deruxtecan (I-DXd) showed high response rates in heavily pretreated ES-SCLC and received FDA breakthrough therapy designation.
From “one-size-fits-all” to subtypes and immunotherapy
The article highlights two developments that changed the field’s trajectory. First, SCLC is now described using four molecular subtypes with distinct transcriptional signatures: SCLC-A, SCLC-N, SCLC-P, and an inflammatory subtype (SCLC-I) that appears most likely to benefit from immune checkpoint inhibitors (ICIs). Second, ICIs represent “the most meaningful advancement in SCLC treatment in over three decades.”
Adding atezolizumab or durvalumab to first-line chemotherapy in ES-SCLC increased median survival by about two months, while also introducing a “survival tail” of long-term responders. Subsequent studies extended benefits into maintenance therapy (IMforte) and, for the first time, into LS-SCLC after chemoradiotherapy (ADRIATIC).
Why relapse remains the pressure point
SCLC is often chemosensitive, but responses are frequently short-lived, leading to near-universal relapse. The authors note a practical split in relapse timing: patients relapsing after six months may be candidates for platinum rechallenge, while relapse within 90 days is associated with poor prognosis.
Historically, second-line treatment relied on topotecan or CAV (cyclophosphamide, doxorubicin, vincristine). Newer agents such as lurbinectedin and amrubicin have not shown an overall survival benefit compared with topotecan or CAV. This ongoing gap after relapse is the main reason targeted approaches are gaining urgency.
DLL3: a target that translated into survival
To move beyond uniform chemotherapy, the article argues that SCLC needs biomarkers overexpressed on tumor cells and minimally present in normal cells. Delta-like ligand 3 (DLL3) fits this model: it is an inhibitory Notch ligand linked to cancer growth, invasion, and metastasis through Notch signaling modulation, and it is overexpressed in neuroendocrine tumors—especially SCLC. High DLL3 expression has been reported in more than 80% of SCLC cases, supporting DLL3-directed approaches such as antibody–drug conjugates (ADCs) and T-cell engagers.
The most prominent example is tarlatamab, a bispecific T-cell engager (BiTE®) that recruits cytotoxic T cells to target DLL3-expressing tumor cells. In the randomized phase 3 DeLLphi-304 study, tarlatamab improved median overall survival to 13.6 months versus 8.3 months with standard chemotherapy in second-line ES-SCLC (HR 0.60, P < 0.001). DLL3 expression was not required for enrollment, and the population included platinum-resistant disease, brain metastases, and many patients previously treated with immunotherapy (71%).
Grade ≥3 adverse events occurred less often than with chemotherapy, but immune-mediated toxicities were notable—cytokine release syndrome in 56% (mostly grade 1–2) and ICANS in about 6%. The authors conclude that these results position tarlatamab as a new second-line standard for ES-SCLC.
B7-H3 and I-DXd: broad expression, strong activity in late lines
B7 homolog 3 (B7-H3/CD276), part of the B7 immune checkpoint regulator family, is presented as another promising SCLC target. The authors describe B7-H3 as integral to tumor growth, metastasis, immune evasion, and therapy resistance. Unlike DLL3 (which varies across subtypes), B7-H3 is described as consistently overexpressed across all four SCLC subtypes, and higher expression correlates with poor prognosis.
In the phase 2 IDEATE-Lung01 study, the ADC ifinatamab deruxtecan (I-DXd) showed “exceptional efficacy” in heavily pretreated ES-SCLC. In patients with at least two prior lines of therapy (76% previously treated with immunotherapy), the 12 mg/kg cohort achieved a confirmed objective response rate of 54.8%, median progression-free survival of 5.5 months, and median overall survival of 11.8 months. The article also notes clinically meaningful responses in patients with brain metastases.
Practical implications: what to study next
Two points are especially relevant for research planning. First, responses to both tarlatamab and I-DXd were observed regardless of DLL3 and B7-H3 expression levels. Second, when evaluating predictors of chemoimmunotherapy efficacy, DLL3 expression did not correlate with response, while B7-H3 did; elevated B7-H3 is also linked to reduced survival and diminished CD8+ T-cell function, suggesting a dual role as a therapeutic target and potential prognostic biomarker.
Looking ahead, the authors highlight practical challenges: optimizing sequencing and combinations to address rapid resistance, expanding these strategies into first-line settings, managing BiTE-specific toxicities, and developing predictive biomarkers for better patient selection. Beyond DLL3 and B7-H3, they note that ADCs targeting Trop2 and seizure protein 6 (SEZ6) are in development, suggesting a broader pipeline is emerging.
As the authors put it, “For the first time, the narrative surrounding SCLC is characterized not by despair but by cautious optimism.”
The translation of the preceding English text in Bosnian:
Karcinom malih ćelija pluća (SCLC) je neuroendokrini karcinom pluća snažno povezan s izloženošću duvanu. Čini oko 15% svih karcinoma pluća, uz približno 150.000 novih dijagnoza godišnje širom svijeta. Decenijama je predstavljao jedan od najtežih izazova u torakalnoj onkologiji: brza proliferacija tumora, agresivna biologija i kasno postavljanje dijagnoze kod većine pacijenata ograničili su značajniji terapijski napredak.
Čak i u ograničenom stadiju SCLC-a (LS-SCLC), operacija je izvodljiva u manje od 5% slučajeva, pa većina pacijenata prima istovremenu kemoradioterapiju kao liječenje s kurativnom namjerom. U proširenom stadiju SCLC-a (ES-SCLC), platina–etopozid dugo je bio standard prve linije, ali je ukupno preživljavanje ostalo ispod 12 mjeseci. Uz malo novih opcija, SCLC je opisan kao „rijetka/orfanska bolest” i zahtjevno područje za razvoj lijekova.
Prije imunoterapije, značajni pomaci u ES-SCLC-u odnosili su se na radioterapijske strategije i prevenciju metastaza u mozgu: konsolidacijska torakalna radioterapija kod pacijenata koji odgovore na kemoterapiju, uz profilaktičko zračenje mozga (PCI) ili MRI nadzor mozga—što je važno jer više od 50% pacijenata na kraju razvije intrakranijalne metastaze.
Ključne poruke
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Molekularno podtipiziranje i imunoterapija promijenili su način na koji istraživači razmišljaju o SCLC-u.
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Tarlatamab usmjeren na DLL3 poboljšao je ukupno preživljavanje u odnosu na kemoterapiju u drugoj liniji ES-SCLC-a, uz specifične imunološke toksičnosti koje zahtijevaju pažljivo zbrinjavanje.
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Ifinatamab derukstekan (I-DXd) usmjeren na B7-H3 pokazao je visoke stope odgovora kod intenzivno pretreated ES-SCLC-a i dobio je FDA oznaku „breakthrough therapy”.
Od pristupa „jedno rješenje za sve” do podtipova i imunoterapije
Članak ističe dva razvoja koja su promijenila smjer područja. Prvo, SCLC se sada opisuje kroz četiri molekularna podtipa s različitim transkripcijskim potpisima: SCLC-A, SCLC-N, SCLC-P i inflamatorni podtip (SCLC-I), koji se čini najsklonijim koristi od inhibitora imunoloških kontrolnih tačaka (ICI). Drugo, ICI predstavljaju „najznačajniji napredak u liječenju SCLC-a u više od tri decenije”.
Dodavanje atezolizumaba ili durvalumaba kemoterapiji prve linije u ES-SCLC-u povećalo je medijanu preživljavanja za oko dva mjeseca, uz pojavu „repnog” dijela krive preživljavanja kod dugotrajnih respondera. Naredne studije proširile su korist na terapiju održavanja (IMforte) i, prvi put, na LS-SCLC nakon kemoradioterapije (ADRIATIC).
Zašto recidiv ostaje ključni problem
SCLC je često osjetljiv na kemoterapiju, ali su odgovori često kratkotrajni, što dovodi do gotovo univerzalnog recidiva. Autori navode praktičnu podjelu prema vremenu recidiva: pacijenti kod kojih se bolest vrati nakon šest mjeseci mogu biti kandidati za ponovnu primjenu platinskog režima, dok je recidiv unutar 90 dana povezan s lošom prognozom.
Historijski, liječenje druge linije oslanjalo se na topotekan ili CAV (ciklofosfamid, doksorubicin, vinkristin). Noviji lijekovi poput lurbinektedina i amrubicina nisu pokazali korist u ukupnom preživljavanju u poređenju s topotekanom ili CAV-om. Ovaj trajni jaz nakon recidiva glavni je razlog zbog kojeg ciljani pristupi dobijaju na hitnosti.
DLL3: meta koja se pretočila u bolje preživljavanje
Da bi se prešlo dalje od uniformne kemoterapije, članak navodi da su SCLC-u potrebni biomarkeri koji su prekomjerno izraženi na tumorskim ćelijama, a minimalno prisutni u normalnim ćelijama. Delta-like ligand 3 (DLL3) uklapa se u ovaj model: riječ je o inhibitornom Notch ligandu povezanom s rastom raka, invazijom i metastaziranjem kroz modulaciju Notch signalizacije, a prekomjerno je izražen u neuroendokrinim tumorima—posebno u SCLC-u. Visoka ekspresija DLL3 zabilježena je u više od 80% slučajeva SCLC-a, što podržava DLL3-usmjerene pristupe poput antitijelo–lijek konjugata (ADC) i T-ćelijskih „engagera”.
Najistaknutiji primjer je tarlatamab, bispecifični T-ćelijski „engager” (BiTE®) koji regrutuje citotoksične T ćelije da ciljaju tumorske ćelije koje eksprimiraju DLL3. U randomiziranoj fazi 3 studiji DeLLphi-304, tarlatamab je poboljšao medijanu ukupnog preživljavanja na 13,6 mjeseci u odnosu na 8,3 mjeseca uz standardnu hemoterapiju u drugoj liniji ES-SCLC-a (HR 0,60, P < 0,001). Ekspresija DLL3 nije bila uslov za uključivanje, a populacija je uključivala platina-rezistentnu bolest, metastaze u mozgu i veliki udio pacijenata prethodno liječenih imunoterapijom (71%).
Neželjeni događaji stepena ≥3 bili su rjeđi nego uz kemoterapiju, ali su imunološki posredovane toksičnosti bile izražene—sindrom oslobađanja citokina u 56% (uglavnom stepen 1–2) i ICANS u oko 6%. Autori zaključuju da ovi rezultati pozicioniraju tarlatamab kao novi standard druge linije za ES-SCLC.
B7-H3 i I-DXd: široka ekspresija, snažna aktivnost u kasnijim linijama
Homolog B7 3 (B7-H3/CD276), dio porodice B7 regulatora imunoloških kontrolnih tačaka, predstavljen je kao još jedna obećavajuća meta u SCLC-u. Autori opisuju B7-H3 kao važan za rast tumora, metastaziranje, izbjegavanje imunog odgovora i otpornost na terapiju. Za razliku od DLL3 (koji varira među podtipovima), B7-H3 je opisan kao dosljedno prekomjerno izražen u sva četiri SCLC podtipa, a viša ekspresija korelira s lošijom prognozom.
U fazi 2 studiji IDEATE-Lung01, ADC ifinatamab derukstekan (I-DXd) pokazao je „izuzetnu efikasnost” kod intenzivno pretreated ES-SCLC-a. Kod pacijenata s najmanje dvije prethodne linije terapije (76% prethodno liječeno imunoterapijom), kohorta od 12 mg/kg postigla je potvrđenu stopu objektivnog odgovora od 54,8%, medijanu preživljavanja bez progresije od 5,5 mjeseci i medijanu ukupnog preživljavanja od 11,8 mjeseci. Članak također navodi klinički značajne odgovore kod pacijenata s metastazama u mozgu.
Praktične implikacije: šta dalje istraživati
Dva su zaključka posebno važna za planiranje istraživanja. Prvo, odgovori na tarlatamab i I-DXd zabilježeni su bez obzira na nivo ekspresije DLL3 i B7-H3. Drugo, pri procjeni prediktora efikasnosti kemoimunoterapije, ekspresija DLL3 nije korelirala s odgovorom, dok je B7-H3 korelirao; povišeni B7-H3 također je povezan sa smanjenim preživljavanjem i oslabljenom funkcijom CD8+ T ćelija, što sugerira dvostruku ulogu—terapijske mete i potencijalnog prognostičkog biomarkera.
Gledajući unaprijed, autori ističu praktične izazove: optimizaciju sekvenciranja i kombinacija kako bi se prevazišla brza rezistencija, širenje ovih strategija u prvu liniju liječenja, upravljanje BiTE-specifičnim toksičnostima te razvoj prediktivnih biomarkera za bolju selekciju pacijenata. Osim DLL3 i B7-H3, navode da su u razvoju i ADC-ovi usmjereni na Trop2 i protein 6 povezan sa napadima (SEZ6), što sugerira da se razvija širi terapijski „pipeline”.
Kako autori navode: „Po prvi put, narativ o SCLC-u ne obilježava očaj, već oprezni optimizam.”
Reference:
Krešimir Tomić, Semir Vranić
Small cell lung cancer (SCLC): At the door of targeted therapies.
Biomol Biomed [Internet]. 2025 Aug. 29 [cited 2025 Dec. 22];26(1):1–4.
Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/13195
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