In the last year and a half, we witnessed several drug approvals and major advances in both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). These have spanned various therapeutic modalities, including targeted agents, immunotherapy, and antibody-drug conjugates (ADCs). The aim of this narrative is to highlight some of these advances and how they impact the current treatment paradigm for lung cancer (rather than serve as an exhaustive review). 

Small cell lung cancer

The approval of tarlatamab, a DLL3‑directed bispecific T‑cell engager, in relapsed SCLC in 2025, represents a historic turning point in oncology. Relapsed SCLC has historically been characterized by poor responses to treatment and dismal outcomes. The registrational DeLLphi-304 phase 3 randomized global trial compared tarlatamab with standard second‑line chemotherapy in patients with relapsed SCLC after platinum therapy.[1] Treatment with tarlatamab led to a significantly longer overall survival (OS) than chemotherapy (median of 13.6 months vs. 8.3 months) with a tolerable adverse event profile. Building on this success, results from the  DeLLphi-303 trial, which randomized tarlatamab in combination with atezolizumab or durvulumab in the first-line maintenance setting, demonstrated a historically unprecedented median OS of 25.3 months. The addition of an immune checkpoint inhibitor during maintenance therapy demonstrated a manageable safety profile, without new safety signals.[2) Confirmation of these findings in ongoing trials such as the DeLLphi-305 (maintenance setting), and 312 (first-line in combination with chemotherapy and immunotherapy) is awaited. If positive, these results will undoubtedly represent a major shift in the treatment paradigm for extensive-stage SCLC. Similarly, results from the DeLLphi-306, which is evaluating tarlatamab in limited-stage SCLC as a consolidation strategy following chemoradiation with definitive intent, are also eagerly awaited.  

Tarlatamab, being a T-cell engaging bispecific, is associated with a risk of causing CRS and ICANS through immune activation.[3] In DeLLphi‑300, a sub-study compared the incidence of adverse events in patients receiving tarlatamab with 6‑hour outpatient monitoring during cycle 1 versus those receiving 48‑hour inpatient monitoring.[4] Patients monitored for 6 hours post-infusion as outpatients demonstrated a very similar safety profile to those monitored inpatient. The outpatient group with 6-8 hours of monitoring showed no increase in the incidence of CRS, with most grade 1 and 2 events being manageable with dexamethasone. This study demonstrates that tarlatamab can be safely administered with 6-8 hour outpatient monitoring, without additional CRS severity or hospitalization risk. These results led to the revision of the FDA label, changing the previously required 20-hour monitoring window to 6-8 hours, in September 2026. Shorter monitoring periods, as low as 1-2 hours, and extended dosing intervals of tarlatamab are also being actively studied, with preliminary results suggesting no adverse safety signals (Goldman J et al. DeLLphi-309, WCLC 2026). Although these data lend support to outpatient administration of the drug - which we anticipate will increase its uptake - the need for careful patient selection and close monitoring remains a pivotal requirement to successfully implement treatment with tarlatamab**.** 

The year 2025 also witnessed the approval of lurbinectedin plus atezolizumab as the first effective maintenance regimen in extensive‑stage SCLC based on results from the prospective,  randomized, phase III IM-FORTE trial, which demonstrated improvements in both progression-free survival (PFS) and OS.[5] While this remains an attractive treatment option for patients with SCLC, how this regimen will fit into the evolving treatment paradigm for SCLC as bispecifics move into the front-line setting with decreased monitoring requirements is still unclear. 

Finally, several ADCs, such as those targeting SEZ6, DLL3, and B7H3 have shown impressive activity in relapsed SCLC.[6–8] Among these, infitamab deruxtecan is currently under review by the FDA for approval. The optimal sequencing of these agents and appropriate combination strategy will undoubtedly remain a major focus of research over the next few years. Collectively, these developments signal a new era in SCLC and show that it is possible to achieve durable survival benefit in cancers that have historically been considered recalcitrant with the right therapeutic strategy. 

Non-small cell lung cancer

Targeted therapies

NSCLC continues to remain the poster child for personalized medicine. While we witnessed the approval of combination therapy regimens for EGFR-mutated lung cancer in 2024, the role of these therapies as preferred front-line options for treating patients with metastatic disease was cemented further in 2025. Updated results from FLAURA2 data demonstrated that the addition of platinum-based chemotherapy to osimertinib in comparison to osimertinib alone led to a significant OS benefit.[9] The combination showed a median OS of 47.5 months versus 37.6 months with osimertinib alone. The regimen also demonstrated better CNS control with the combination compared to osimertinib alone.

The MARIPOSA trial similarly demonstrated a PFS and OS benefit with amivantamab and lazertinib in patients with EGFR-mutated NSCLC in the first-line setting, leading to its approval in 2024.[10]  However, given that this regimen was associated with a high incidence of infusion reactions and cutaneous adverse events, supportive care studies such as SKIPPirr (for infusion reactions) and COCOON (dermatological prophylaxis) were initiated to determine optimal prophylactic interventions to mitigate these adverse events.[11,12] Results from the COCOON trial showed significantly lower rates of high-grade rashes and scalp toxicities with the combination of amivantamab and lazertinib when patients followed enhanced dermatological prophylactic strategies. Further building on the theme of improving patient experience and minimizing “time-toxicity” associated with treatment, the PALOMA 3 trial showed comparable outcomes with intravenous and subcutaneous formulations of amivantamab.[13] This eventually led to the FDA approval of the subcutaneous formulation in late 2025. The development of the subcutaneous formulation of amivantamab and insights gained from COCOON  represent meaningful advances in supportive care by focusing on treatment delivery and adverse event prevention and management, with the potential to greatly improve patient experience. 

The role of amivantamab in managing EGFR-mutated lung cancers was further supported by data from the Chrysalis-2 trial, which is a multi-arm trial that demonstrated clinically meaningful activity with the combination of amivantamab and lazertinib, post-TKI, in patients with classical mutations, and also in patients with uncommon EGFR mutations.[14,15] These results, in combination with efficacy data from PAPILLON in exon 20 mutated lung cancer, reinforce the role of amivantamab as a “pan-EGFR” treatment strategy.[16]

We also saw an expansion of the targeted therapy armamentarium in NSCLC in 2025-2026. Zongertinib, a small molecule that targets ERBB2 (HER2) alterations, received accelerated approval in August 2025 and front-line use approval in early 2026 through the FDA voucher program.[17] The overall response rate with this drug was 76% in treatment-naive patients with a median PFS of 14.4 months. Notably, this approval was quickly followed by the accelerated approval of sevabertinib, another oral HER2-directed TKI in the second-line setting (and subsequently the first-line setting in September 2026).[18] Confirmatory randomized trials with these TKIs in the front-line setting are ongoing. Full results from Destiny Lung-04, a phase III randomized trial examining the role of trastuzumab-deruxtecan (T-dxd) in the front-line setting, were presented in September 2026 at the World Lung Cancer Conference (Rotow et al. WCLC 2026). The study was positive for PFS against chemotherapy and immunotherapy. T-dxd is the first targeted therapy to have received approval for the management of ERBB2-mutated NSCLC back in 2022, in the second-line and beyond setting.  Notably, T-dxd also received approval for the management of ERBB2-overexpressing NSCLC (by IHC).[19]

Among other oral TKIs approved in 2025 is taltrectinib, which showed impressive ROS1 activity in conjunction with an improved toxicity profile.[20] Taltrectinib possesses activity against ROS1 mutations that confer resistance to earlier-generation TKIs such as crizotinib and entrectinib (including the G2032R mutation), and higher selectivity against ROS1 - thereby reducing CNS off‑target binding and minimizing MET/TRK inhibition-associated side effects such as neurologic toxicity and edema. Zidesamtinib, another highly active and selective ROS1 inhibitor also received FDA approval in 2026. The drug also demonstrated impressive efficacy in the first-line setting (Drilon et al. ARROS-1, WCLC 2026) and post-taletrectinib. More mature data from these trials and insights into resistance mechanisms will hopefully guide the optimal sequencing strategy of these agents. 

Sunvozertinib,  an EGFR TKI, was also approved in 2025 for managing exon 20 mutated disease - an entity against which 3rd-generation inhibitors like osimertinib possess little to no activity.[21] In data presented at ASCO 2026, sunvozertinib proved to be superior to chemotherapy alone in the front-line setting.[22] While the drug was not available for distribution in US markets for more than a year following its approval, its availability is being anticipated in the latter part of 2026 (following its acquisition by AstraZeneca). Zipalertinib, another TKI with activity against EGFR-exon 20 mutations, also showed promising first-line efficacy in conjunction with chemotherapy (Kim et al. REZILENT 3, WCLC, 2026). Finally, the activity of these and other TKIs, such as firmonertinib, is also being studied in patients with rare mutations in EGFR that are classifiable as PACC mutations.[23] These findings collectively represent an evolving paradigm for managing EGFR-mutated NSCLCs. 

Among previously approved targeted therapies, data from several clinical trials showed feasibility, survival benefit, and impressive efficacy with ALK (LORIN: lorlatinib in neoadjuvant setting), EGFR (NEOADAURA: osimertinib in neoadjuvant setting), and RET (LIBRETTO 432: selpercatinib in adjuvant setting) inhibitors in the peri-operative space.[24–26] These data further cement the role of peri-operative targeted therapies in clinical practice for an expanding range of targets.

ADCs and other bispecifics

Antibody-drug conjugates (ADCs) received prominent FDA approvals in 2025, carving out a role for these drugs in the mainstream management of certain biomarker-selected NSCLC patients. These included the approval of datopotamab deruxtecan (Dato-DXd) for EGFR-mutated NSCLC post-TKI and platinum-based chemotherapy.[27] Similarly, telisotuzumab vedotin, an ADC that targets MET, received approval in May 2025 for MET overexpressing NSCLC.[28] Sacituzumab Tirumotecan (Sac-TMT) examined in the Chinese OptiTROP-Lung04 trial demonstrated superiority of Sac-TMT over chemotherapy in post-TKI EGFR-mutated NSCLCs.[29] Sac‑TMT showed a 8.3 months PFS in comparison to chemotherapy at 4.3 months (Zhang et al). In conjunction with pooled data from Tropion Lung 01 and 05 trials, these results highlight TROP2 as an attractive target in the EGFR-mutated NSCLC. The emergence of these ADCs further reinforces the need for comprehensive and multidimensional (DNA and IHC)  biomarker testing in NSCLC. Data from correlative analyses from studies such as Tropion-Lung 01 also suggest that novel diagnostic approaches utilizing digital and computational pathology platforms may be necessary to develop biomarkers with improved predictive value in the near future.[30] 

Combination therapies emerging in the targeted therapy space include adagrasib and pembrolizumab as first-line treatment in the KRAS-mutant NSCLC (KRYSTAL 7).[31] The KRYSTAL-7 trial showed an overall response rate of 44% and a median PFS of 11 months. It should, however, be noted that the toxicity profile with this regimen, specifically transaminitis, was a concern. Approximately 40% of patients experienced AST/ALT elevations. With multiple studies exploring combinations in this space, especially with newer-generation KRAS G12C inhibitors (such as olomorasib, calderasib, divarisib, etc.) with relatively better hepatotoxicity profiles (based on early data), the role of combination therapies in this patient population and the optimal sequencing of therapies remains to be determined. 

Several PD-(L)1xVEGF bispecifics are currently being actively studied in NSCLC. Among these, ivonescimab, pumitamig, and PF-08634404 have demonstrated promising efficacy signals in 2025 and 2026.[32–35] Among these,  ivonescimab has shown significant survival benefit across different histologies in large randomized trials. Ivonescimab was shown to be superior to chemotherapy alone in EGFR-mutated NSCLC post-TKI in the HARMONi-A trial.[32] The drug also demonstrated a significant survival benefit in the Chinese HARMONi-6 trial, in patients with metastatic squamous cell carcinoma in the first-line setting.[33] With positive OS results from HARMONi-2 (vs. pembrolizumab with PD-L1 positive NSCLC) also being recently reported (Zhou et al. HARMONi-2, WCLC 2026), results from global HARMONi trials and other PD-(L)1xVEGF bispecifics (such as pumitamig) are eagerly awaited - with the hope that these results will represent a meaningful advance in the field. 

It is worth noting that the advances summarized in this article are largely restricted to large randomized trials and FDA approvals. An exhaustive amount of research with other novel treatment and diagnostic modalities was also witnessed in the past 2 years. These span multiple modalities such as novel immunotherapies, small molecules targeting RAS proteins that were previously thought to be undruggable, vaccines, and bispecifics - to name a few. For instance, impressive efficacy was reported with daroxonrasib - a pan-RAS inhibitor in both pancreatic and RAS-mutated NSCLCs in 2026.[36] With these advances, the goal of treating incurable lung cancer as a chronic illness definitely appears closer than ever.   

References

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