From the PACIFIC to the ADRIATIC: a literature review of 38 years of failed maintenance trials in small cell lung cancer post-chemoradiation

Introduction

Small cell lung cancer (SCLC), an infamously aggressive high-grade neuroendocrine malignancy that is highly associated with tobacco use, makes up approximately 15% of all lung cancer diagnoses, with 30% of these cases being limited stage disease (1,2). SCLC has historically been divided into limited stage disease, or tumor located in the thorax within one radiation field, and extensive stage disease, or distant metastases or not confined to one radiation field (3). The current standard of care (SOC) treatment of limited stage SCLC (LS-SCLC) is platinum-based chemotherapy given concurrently with radiotherapy with or without the addition of prophylactic brain irradiation (4,5). However, in spite of SCLC’s initially high chemosensitivity and radiosensitivity, the majority of patients relapse within the first two years of diagnosis, with the median overall survival (OS) with chemoradiotherapy being 25–30 months in LS-SCLC (6). In addition, patients with metastatic SCLC on chemotherapy have been shown to have a median OS of 9–11 months (7-12). Unfortunately, in spite of intensive research efforts beginning in the 1970s, little progress has been made in the treatment of SCLC over the past several decades. Thus, in spite of ongoing innovation and promising new therapies, both LS-SCLC and extensive stage SCLC (ES-SCLC) have continued to represent unmet needs and an area of slow progress in the world of oncology.

Previous reviews have explored novel treatments as well as treatment strategies in SCLC, described immunotherapy’s role in both LS-SCLC and ES-SCLC, and discussed maintenance therapy in ES-SCLC (13-17). Here, our narrative review expands upon these reviews by describing various maintenance trials in LS-SCLC, providing an overview of both positive and negative maintenance trials, and proposing explanations for the ADRIATIC trial’s success following a history of numerous failed trials. We present this article in accordance with the Narrative Review reporting checklist (available at https://actr.amegroups.com/article/view/10.21037/actr-25-71/rc).

Methods

In this review, we initiated a search of relevant clinical trials via PubMed, ClinicalTrials.gov, and major scientific proceedings, including the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the World Conference on Lung Cancer (WCLC). We searched for trials examining immunotherapy’s role in the treatment of both limited and ES-SCLC as well as those examining the utility of immunotherapy and other novel therapies as maintenance therapy in LS-SCLC. The trials identified spanned the period of June 1986 to May 2025. Only abstracts and publications in English were considered eligible (Table 1).

SCLC in the era of precision medicine and the role of immunotherapy

SCLC has long been considered a relatively homogenous disease, thought to represent a single morphological type. In contrast, non-small cell lung cancer (NSCLC) has been front and center in the era of precision medicine, with the treatment of NSCLC now being guided by ever-advancing knowledge about tumor biology, molecular profiling, and other patient and tumor-specific characteristics. The individualized approach to therapy afforded by these advances in NSCLC has not been the story in SCLC, which has been defined by relatively slow progress over the past few decades with comparatively few advances in treatment. However, recent progress in the understanding of the molecular and genomic heterogeneity of SCLC has shed light on potential therapeutic targets and has raised the possibility of a more personalized approach to the treatment of SCLC.

The development of SCLC is now known to be highly complex, with several oncogenic driver mutations associated with its development. In addition to near universal loss of function mutations in tumor suppression genes, tumor protein 53 (TP53) and retinoblastoma 1 (RB1), SCLC has also been associated with loss of function mutations in RB1 and phosphatase and tensin homolog (PTEN), which then leads to dysregulation of several signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/Ak strain transforming (AKT)/mammalian target of rapamycin (mTOR), rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK), and neurogenic locus notch homolog protein 1 (NOTCH1) (18-20). Furthermore, it has also been associated with activating mutations in MYC, TP53, RB1, PTEN, and NOTCH1 (20). In spite of the array of mutations associated with the development of SCLC, there has largely remained a lack of viable therapeutic targets and consequently of targeted therapies that have proven useful in the treatment of SCLC, although many studies are still ongoing.

Immunotherapy has recently emerged as a notably promising player in the treatment of SCLC. SCLC is more highly associated with smoking, which has historically been associated with higher expression of programmed death ligand 1 (PD-L1), and thus responsiveness to immune checkpoint blockade, as seen in NSCLC (21,22). Although SCLC is not associated with high PD-L1 expression, SCLC is associated with high tumor mutational burden, also known to confer responsiveness to immunotherapy (18,23). In spite of less favorable results from earlier trials evaluating immunotherapy as monotherapy in the treatment of SCLC, several trials since, including the IMpower133 and CASPIAN trials, and most recently, the ADRIATIC trial, have demonstrated immunotherapy’s important role in the treatment of SCLC (24).

Immunotherapy makes its mark in the treatment of ES-SCLC

In the global phase 3 IMpower133 trial evaluating induction carboplatin and etoposide in combination with atezolizumab, a humanized monoclonal anti-PD-L1 antibody, followed by maintenance atezolizumab versus placebo, the atezolizumab and chemotherapy combination group demonstrated significantly longer OS and progression-free survival (PFS) compared to the placebo group (25). These results were the first to demonstrate the utility of immunotherapy used in combination with chemotherapy in the first-line treatment of ES-SCLC. The global phase 3 CASPIAN trial then followed, evaluating durvalumab, a humanized potent, high-affinity monoclonal anti-PD-L1 antibody, with or without tremelimumab, a cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibody, in combination with cisplatin or carboplatin with etoposide in patients with ES-SCLC. Updated results showed that durvalumab in combination with platinum-etoposide demonstrated sustained OS benefit, confirming the benefit of immunotherapy used in combination with chemotherapy and solidifying its role as the SOC first-line treatment of ES-SCLC (26,27). The global phase 3 KEYNOTE-604 trial then evaluated pembrolizumab, an inhibitor of programmed cell death 1 (PD-1), in combination with chemotherapy in the first-line treatment of SCLC, unfortunately showing no OS benefit with pembrolizumab and chemotherapy (28). The multicenter phase 3 CAPSTONE-1 trial conducted in China then evaluated novel PD-L1 inhibitor adebrelimab in combination with chemotherapy in the first-line treatment of ES-SCLC, demonstrating OS benefit in the adebrelimab and chemotherapy group (29). Similarly, the global phase 3 ASTRUM-005 trial evaluated serplulimab, a PD-1 inhibitor, in combination with chemotherapy in the first-line treatment of ES-SCLC, demonstrating OS benefit in the serplulimab and chemotherapy group (30).

Although these trials have largely shown survival benefit with the addition of immunotherapy to front-line treatment of ES-SCLC with chemotherapy, the benefit conferred by this treatment approach is limited, and raises the question of a consolidation or maintenance approach in extending or improving response to treatment. Importantly, the role of immunotherapy and other agents as maintenance therapy was previously not well defined, and gave rise to various maintenance therapy trials.

The global phase 3 CheckMate 451 trial explored the potential to use nivolumab and ipilimumab, anti-PD-1 antibody and anti-CTLA-4 antibody, respectively, following first line platinum-based chemotherapy. Unfortunately, the primary end point of this study was not met, and its overall negative result has been attributed to the toxicity associated with nivolumab and ipilimumab combination therapy, which then led to reduced drug exposure in the combination arm (31). As such, nivolumab and ipilimumab are not approved for use as maintenance therapy in ES-SCLC. Unfortunately, pembrolizumab’s story is not different from that of nivolumab and ipilimumab. In a phase 2 study, patients with ES-SCLC who had undergone induction chemotherapy showed little benefit with pembrolizumab maintenance therapy, with a median PFS of 1.4 months [95% confidence interval (CI): 1.3–2.8] and a 1-year PFS of 13% (32).

Failed maintenance trials in LS-SCLC

Similar to the CheckMate 451 trial, the STIMULI trial evaluated nivolumab and ipilimumab as consolidation therapy in the treatment of LS-SCLC. In this phase 2 trial, patients with LS-SCLC who had prior concurrent chemoradiotherapy (cCRT) followed by prophylactic cranial irradiation (PCI) were randomized to nivolumab and ipilimumab every three weeks followed by nivolumab maintenance every two weeks for up to 12 months or to observation. The primary endpoint was locally-assessed PFS (33). At the time of data cutoff, the immunotherapy maintenance group failed to show PFS benefit, with a median PFS of 10.7 months [95% CI: 7–not evaluable (NE)] in the immunotherapy group and 14.5 months (95% CI: 8.2–NE) in the observation group, with a hazard ratio (HR) of 1.02 (95% CI: 0.66–1.58; P=0.93). After a median follow-up time of 35 months, median OS was not reached in the immunotherapy group (95% CI: 26.1–NE) compared to 32.1 months (95% CI: 26.1–NE) in the observation group, again failing to show benefit, with a HR of 0.95 (95% CI: 0.59–1.52; P=0.82). As such, the role of immunotherapy as maintenance therapy in LS-SCLC continued to remain unclear (33).

As with ES-SCLC, various other agents have also failed to demonstrate benefit as maintenance therapy in LS-SCLC. Decades spent on evaluating various consolidation regimens have been haunted by successive failures. For example, the BR.20 trial evaluated vandetanib, an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR2), as maintenance therapy in 107 patients with SCLC (46 of whom had LS-SCLC) who had achieved complete or partial response with first line therapy. This was overall a negative study, finding no OS or PFS benefit in patients treated with vandetanib (34). A Southwest Oncology Group (SWOG) study evaluating recombinant interferon alfa-2a (rIFN alpha-2a) as maintenance therapy in patients with LS-SCLC who had achieved objective response to chemoradiotherapy was also negative due to failure to tolerate and complete therapy (35).

These and other failed trials are a testament to the impossibility and challenge seemingly inherent to the treatment of SCLC, particularly in the maintenance setting (Figure 1).

Figure 1 An overview of decades of failed maintenance trials in LS-SCLC. BCG, Bacillus Calmette-Guérin; Bec2, mitumomab; CR, complete remission; DFS, disease-free survival; ES, extensive stage; IFN, interferon; LS, limited stage; nIFN, native interferon; NM, no maintenance; NR, non-remission; ORR, objective response rate; PFS, progression-free survival; PR, partial remission; PVP16, etoposide; rIFN, recombinant interferon; RT, radiotherapy; SCLC, small cell lung cancer; TIW, three times per week.

Durvalumab as maintenance therapy in LS-SCLC: the ADRIATIC trial

Interestingly, maintenance therapy has become increasingly important in NSCLC, as demonstrated by the PACIFIC trial, which revealed the utility of durvalumab, a humanized, selective, high-affinity monoclonal IgG antibody against PD-L1, as consolidation post cCRT in locally-advanced NSCLC (36). The PACIFIC trial’s promising results then gave rise to the question of its analogous role as maintenance therapy in SCLC.

Highly anticipated results from the ADRIATIC trial were presented at the 2024 ASCO Annual Meeting Plenary Session. In this global multicenter phase 3 trial, 730 participants with stage I–III LS-SCLC who had not progressed following cCRT were randomized 1:1:1 to durvalumab 1,500 mg every 4 weeks (N=264), placebo every 4 weeks (N=266), or durvalumab 1,500 mg every 4 weeks and tremelimumab 75 mg every 4 weeks for four doses followed by durvalumab 1,500 mg every 4 weeks (N=200). Stratification factors included disease stage (I/II versus III), and PCI (yes versus no). Dual primary endpoints in the durvalumab versus placebo groups included OS and PFS assessed by blinded independent central review (BICR). Key secondary endpoints in the durvalumab and tremelimumab versus placebo groups included OS and PFS assessed by BICR. Other secondary endpoints included OS and PFS landmarks and safety. The analysis of OS and PFS met prespecified efficacy boundaries for the durvalumab versus placebo groups, while the durvalumab and tremelimumab arm remains blinded until the next planned analysis (37).

After a median follow-up time of 37.2 months, the durvalumab group demonstrated a median OS of 55.9 months (95% CI: 37.3–NE) compared to 33.4 months (95% CI: 25.5–39.9) in the placebo group, with a HR of 0.73 (95% CI: 0.57–0.93; P=0.01). After a median duration of follow-up of 27.6 months, the durvalumab group demonstrated a median PFS of 16.6 months (95% CI: 10.2–28.2) compared to 9.2 months (95% CI: 7.4–12.9) in the placebo group, with a HR of 0.76 (95% CI: 0.61–0.95; P=0.02). Treatment benefits were overall consistent across predefined participant subgroups. Among those who had undergone PCI, the 3-year OS rate was 62.1% in the durvalumab group compared to 56.5% in the placebo group. Among those who had not undergone PCI, the 3-year OS rate was 50.2% in the durvalumab group compared to 37.3% in the placebo group. Benefit was also retained across both cisplatin and carboplatin-based chemotherapy groups. The 3-year OS rate for those who had received carboplatin was 65.3% in the durvalumab group compared to 46.7% in the placebo group. Interestingly, results were less favorable in the cisplatin group. The 3-year OS rate for those who had received cisplatin was 52.1% in the durvalumab group compared to 48.1% in the placebo group. Benefit with durvalumab was also retained across both once and twice-daily radiotherapy schedules (37).

Furthermore, durvalumab was generally well-tolerated, with adverse events consistent with known safety profiles. Adverse events of grade 3 or 4 were observed in 24.4% of patients in the durvalumab group and 24.2% of patients in the placebo group. Although higher rates of grade 3 and 4 treatment-related adverse events were seen in subgroups who had received PCI as well as carboplatin, treatment discontinuation rates were similar across these groups. Moreover, significantly increased rates of radiation pneumonitis were not seen in durvalumab groups (37).

Discussion

The results of the ADRIATIC trial were the first to demonstrate immunotherapy’s efficacy as maintenance therapy following cCRT in patients with LS-SCLC and have paved the way for durvalumab consolidation therapy to become the new SOC in this space.

This triumph is curious not only in the context of immunotherapy’s still largely unknown and undefined role in the front-line treatment of LS-SCLC, but also in light of decades of failed maintenance trials in LS-SCLC. The nearly 2-year OS benefit won by durvalumab maintenance therapy compels us to explore the mechanisms underlying its success and its implications for the future of SCLC treatment.

Although, as mentioned, SCLC has been shown to possess certain characteristics thought to be linked to responsiveness to immunotherapy, SCLC has previously been defined as an “immune cold” tumor, owing to its association with a relatively uninflamed tumor microenvironment (TME), reduced PD-L1 expression, downregulation of major histocompatibility complex molecules, and ability to induce immunosuppressive effects (38,39). Thus, in spite of its association with a high tumor mutational burden, SCLC has historically demonstrated limited response to immunotherapy. Even as immunotherapy’s role in SCLC became clear with the successes seen in the IMpower133, CASPIAN, and ADRIATIC trials, the mechanism underlying immunotherapy’s newfound success has remained uncertain.

Interestingly, the results of the ADRIATIC trial closely parallel those of the PACIFIC trial, albeit in the SCLC space. As mentioned, the PACIFIC trial compared durvalumab to placebo as consolidation therapy in the treatment of patients with locally-advanced NSCLC who had previously undergone treatment with chemoradiotherapy. As such, the efficacy of immunotherapy after initial treatment with chemoradiotherapy seen in both trials raises the question of whether prior treatment with chemoradiotherapy renders tumors more responsive to the action of immunotherapy and effectively primes tumors for subsequent treatment with immunotherapy.

Radiation therapy has been widely shown to have immunogenic effects, with the ability to modulate the TME. It has been shown to liberate tumor neoantigens for CD8⁺ T-cell priming, induce immunogenic cell death via stimulation of damage-associated molecular patterns, upregulate signals promoting CD8⁺ T-cell mediated killing, and cause an abscopal tumor response that is thought to be immune-mediated (40,41). These immunogenic effects of radiotherapy are then thought to confer responsiveness to immunotherapy. In contrast, chemotherapy has historically been thought to be immunosuppressive. However, it has since been shown that chemotherapy’s role in the TME is more nuanced, characterized by the ability to act synergistically with immunotherapy via tumor cell killing and TME infiltration with CD8⁺ T cells. As such, chemotherapy has also demonstrated promise as an adjunct to immunotherapy (42).

Although chemotherapy and radiation’s complementary relationship with immunotherapy has not yet been well delineated, particularly in the context of LS-SCLC, the results of the PACIFIC and ADRIATIC trials provide compelling evidence of front-line chemoradiotherapy’s ability to alter the TME such that it becomes more susceptible to the action of immunotherapy. Thus, the success of the ADRIATIC trial may, in part, be attributable to timing the delivery of immunotherapy after tumors are primed to be more responsive to its action.

In addition to the role of prior treatment in rendering tumors more susceptible to treatment with immunotherapy, the mechanism of action employed by various immunotherapy agents may also play a role in their efficacy in SCLC. As seen in the CASPIAN, and IMpower133 trials, atezolizumab and durvalumab, both anti-PD-L1 antibodies, conferred survival benefit in combination with chemotherapy in the first-line treatment of ES-SCLC. Similarly, in the ADRIATIC trial, durvalumab also conferred survival benefit as maintenance therapy in the treatment of LS-SCLC. On the other hand, nivolumab and ipilimumab, anti-PD-1 antibody and anti-CTLA-4 antibody, respectively, did not confer survival benefit in combination with chemotherapy in the first line treatment of ES-SCLC, as seen in the CheckMate 451 trial (31). Similarly, nivolumab and ipilimumab also did not confer a survival benefit as maintenance therapy in the treatment of LS-SCLC, as seen in the STIMULI trial (33).

The discrepancy seen between treatment with anti-PD-L1 antibodies versus anti-PD-1 antibodies in both LS-SCLC and ES-SCLC may be explained by how these drugs interact with the “cold” TME in SCLC. It has been theorized that PD-1 inhibitors may, in general, be more effective by way of their ability to block both the binding of PD-L1 and programmed cell death-ligand 2 (PD-L2), compared to PD-L1 inhibitors, which block only the binding of PD-1 with PD-L1. However, it must be noted that PD-L1 binds both PD-1 as well as CD80, a protein expressed on tumor-associated dendritic cells and an important co-stimulatory molecule that augments T cell activation. As such, PD-L1 inhibitors may mount a more robust anti-tumor immune response via their ability to block PD-L1 on dendritic cells in a TME known to be relatively uninflamed (43). However, although PD-L1 inhibitors seem to have proven more effective in the treatment of SCLC than have PD-1 inhibitors, it has largely been concluded that both agents seem to be comparable in efficacy and tolerability, based on what is known thus far (44,45).

While immunotherapy is undoubtedly a valuable component SCLC treatment, this treatment space is currently devoid of many of the tools that have become increasingly familiar in the treatment of NSCLC. In contrast to NSCLC, for which a variety of biomarkers have become relatively well-established in guiding treatment and predicting response to therapy, the presence and role of biomarkers in guiding the treatment of SCLC has yet to be seen. Importantly, molecular subtyping of SCLC based on expression of certain transcription factors has been proposed as a means to guide therapy selection. Four subtypes of SCLC were described in a study examining transcriptional subtyping in SCLC, wherein investigators examined tumors from patients who largely had limited stage disease. These subtypes include SCLC-A and SCLC-N, which differentially express neuroendocrine genes, and SCLC-P and SCLC-I, which express non-neuroendocrine genes (46).

Neuroendocrine SCLC tumors categorized as SCLC-N and SCLC-A are thought to be driven by neurogenic differentiation factor 1 (NEUROD1) and achaete-scute homolog 1 (ASCL-1), respectively, and are also associated with cellular myelocytomatosis oncogene (cMYC) and TTF1 expression. SCLC-N tumors have been shown to be sensitive to aurora kinase (AURK) inhibitors, with cMYC being a useful biomarker in predicting response to AURK inhibitors. SCLC-A tumors have been shown to be sensitive to B-cell lymphoma 2 (BCL2) inhibitors, with BCL2 being a useful biomarker in predicting response to these therapies. SCLC-P tumors are thought to be driven by POU class 2 homeobox 3 (POU2F3), and have been shown to be sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors, anti-folates, and nucleoside analogues (46).

Interestingly, SCLC-I tumors are defined as an inflamed tumor type, associated with higher epithelial-mesenchymal transition (EMT) expression as well as higher tumor immune cell infiltration, cytolytic activity, human leukocyte antigen (HLA) expression, and immune checkpoint molecules. As such, SCLC-I tumors are thought to be more responsive to Bruton’s tyrosine kinase (BTK) inhibitors as well to immune checkpoint inhibition. Importantly, although the landmark trials described in this review were not powered for subgroup analyses based on the four described subtypes of SCLC, in an analysis of survival trends from IMpower133, it appears that trends in OS benefit were generally retained across all four subtypes in patients treated with chemoimmunotherapy, with a far greater magnitude of benefit seen in SCLC-I tumors, indicating that SCLC-I subtype may be a useful biomarker in predicting response to immunotherapy (46).

Future directions

Although the ADRIATIC trial’s positive results represent an exciting leap forward in LS-SCLC, crowning durvalumab as the maintenance therapy of choice in a treatment landscape marred by a long history of failures, there remains a great deal of work to be done. In the wake of this success, we must not only consider other therapies, including alternative immunotherapies and emerging novel therapies, but we must also reimagine and redesign the sequences of, combinations of, and approach to therapy in the treatment of LS-SCLC.

Other immunotherapy agents and regimens are currently being investigated. In light of atezolizumab’s important role in the front-line treatment of ES-SCLC based on results from the IMpower133 trial, the phase 3 ACHILES trial is currently evaluating atezolizumab as maintenance therapy in the treatment of patients with LS-SCLC who had previously undergone treatment with cCRT (47). The phase 3 IMforte trial was also recently presented at the 2025 ASCO Annual Meeting, which treated patients with ES-SCLC without disease progression following standard induction therapy with atezolizumab, carboplatin, and etoposide, with maintenance lurbinectedin in combination with atezolizumab or atezolizumab alone. A significant OS benefit was seen in the lurbinectedin and atezolizumab maintenance therapy group compared to atezolizumab alone (48). Several trials have also investigated the role of immunotherapy in combination with cCRT followed by maintenance therapy. The phase 2/3 NRG-LU005 trial sought to compare patients with LS-SCLC treated with cCRT alone to those treated with cCRT in combination with atezolizumab followed by atezolizumab consolidation therapy, unfortunately showing no survival benefit with the addition of atezolizumab (49). The phase 2 DOLPHIN trial assesses the efficacy and safety of cCRT in combination with durvalumab, followed by durvalumab maintenance therapy. Importantly, a similar phase 2 trial (NCT03585998) conducted in Korea evaluated cCRT in combination with durvalumab followed by durvalumab maintenance therapy and demonstrated promising efficacy (50).

Alternative sequences of therapy are also being evaluated. For example, a phase 2 trial (NCT05034133) is currently evaluating durvalumab with cisplatin and etoposide in combination, followed by radiation therapy, representing a shift from the long-established SOC induction therapy comprised of concurrent chemotherapy and radiation therapy (51). Additional trials on the role of PCI in the treatment of both ES-SCLC and LS-SCLC are also underway. The SWOG S1827 trial is currently evaluating MRI surveillance with and without PCI in patients with both LS-SCLC and ES-SCLC with no prior brain metastases and a negative MRI following first-line therapy (52). Similarly, the PRIMALung (EORTC-1901) trial seeks to evaluate the role of MRI surveillance with and without PCI in patients with SCLC (53). These possibly paradigm-shifting trials embody an important effort to revise standards of care in SCLC’s nascent era of immunotherapy.

Various novel therapies have also emerged in recent years and may represent exciting and important opportunities for the development of new therapeutic combinations in LS-SCLC. A phase 3 trial (NCT04691063) is currently evaluating SHR-1316, an anti-PD-L1 monoclonal antibody, in combination with cCRT in the treatment of LS-SCLC (54). PARP inhibitors have also demonstrated promising preclinical and clinical data in SCLC, and are thought to act synergistically with immunotherapy (55). The phase 3 KEYLYNK-013 trial is currently evaluating cCRT in combination with pembrolizumab, followed by pembrolizumab with or without olaparib, a PARP inhibitor (56). Other trials involving other PARP inhibitors are also underway. Anti-T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domains (TIGIT) monoclonal antibodies have also arisen as promising contenders in this space, and are also thought to act synergistically with immunotherapy. The phase 2 AdvanTIG-204 trial is currently being conducted, seeking to evaluate the role of OCI, a monoclonal antibody with the ability to bind TIGIT to block interaction with tumor cells, and tislelizumab (TIS), an anti-PD-1 monoclonal antibody in the treatment of LS-SCLC. In this study, investigators will compare cCRT in combination with OCI and TIS followed by OCI and TIS maintenance therapy, cCRT in combination with TIS followed by TIS maintenance therapy, and cCRT alone (57). A similar phase 2 trial is also underway, evaluating atezolizumab and tiragolumab, another anti-TIGIT monoclonal antibody, as consolidation therapy in LS-SCLC (58).

Other promising novel therapies have also arisen in the ES-SCLC space. In recent years, antibody drug conjugates (ADCs), typically composed of a monoclonal antibody covalently attached to a cytotoxic payload via a chemical linker, have emerged as an exciting addition to the world of targeted therapies. Although earlier trials evaluating ADCs in SCLC were plagued by challenges related to toxicity and efficacy, newer ADCs have demonstrated great promise in the treatment of SCLC. The phase 2 IDeate-Lung01 trial evaluating ifinatamab deruxtecan (I-DXd), an antibody targeting B7-H3 linked to a DNA topoisomerase I inhibitor, in the treatment of ES-SCLC is currently ongoing, with recently-presented interim results showing promising clinical efficacy (59). Tarlatamab, a bispecific T-cell engager immunotherapy targeting DLL3 and CD3 to cause T-cell-mediated cancer cell lysis, has also demonstrated its utility in relapsed or refractory SCLC, based on recently published results from the phase 2 DeLLphi-301 trial (48). Several studies are underway to further evaluate tarlatamab’s role in SCLC (60-65). However, the utility of ADCs and bispecific antibodies in the limited stage setting largely remains to be seen and represents an important opportunity for further studies.

Conclusions

After decades of negative trials, the ADRIATIC trial represents an exciting leap forward in the treatment of a notoriously difficult to treat disease. Following in the footsteps of the PACIFIC trial, which established immunotherapy’s role as consolidation therapy in locally-advanced NSCLC, the ADRIATIC trial affirms immunotherapy’s analogous role in LS-SCLC. This success should compel us to continue to reimagine long-established standards of care in SCLC. As such, we eagerly await the results of ongoing trials that will shed light on the utility of novel therapies, combination approaches, and new sequences of therapy that will continue to improve outcomes in patients with SCLC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://actr.amegroups.com/article/view/10.21037/actr-25-71/rc

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-71/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-71/coif). S.H.I.O. serves as an unpaid International Advisory Board member of AME Clinical Trials Review from July 2025 to June 2027. M.N. reports receiving consulting fees from Caris Life Sciences; honoraria from AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Genentech, BMS/Mirati, Takeda, Johnson and Johnson, Boehringer Ingelheim, and Regeneron; and travel support from AnHeart Therapeutics/Nuvation Bio. S.H.I.O. reports receiving consulting fees from Pfizer, Bayer, BMS; honoraria for lectures from Pfizer, Astra Zeneca, DAVA oncology, and OncLive; stock ownership from Nuvalent, MBrace Therapeutics, BlossomHill Therapeutics, and Lilly; and stock options from Nuvation Bio. Z.L.A. reports receiving honoraria for advisory board from Catalyst, Rigel and Johnson and Johnson. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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