Key ASCO 2026 Updates in NSCLC and SCLC

Lung cancer remains one of the most rapidly evolving areas in oncology, with advances in targeted therapy, immunotherapy, and biomarker-driven treatment continuing to reshape clinical practice. At the 2026 American Society of Clinical Oncology Annual Meeting (ASCO 2026), several studies highlighted the expanding role of precision medicine across disease stages, while novel treatment strategies offered new opportunities to improve outcomes in both NSCLC and SCLC. 

During an Advancements in Oncology event coinciding with ASCO 2026, the Oncology Brothers, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, spoke with Narjust Florez, MD, of Dana-Farber Cancer Institute; Stephen Liu, MD, of MedStar Health; and Rami Manochakian, MD, of Mayo Clinic, who shared their insights on the latest updates and advances in thoracic oncology.

Earlier Use of Targeted Therapy

One of the most anticipated presentations at ASCO 2026 was LIBRETTO-432, a phase 3 trial evaluating adjuvant selpercatinib in patients with resected RET fusion–positive NSCLC.¹ Among patients with stage II–IIIA disease, adjuvant selpercatinib reduced the risk of recurrence, progression, or death by 83% compared with placebo (HR, 0.17; P < .001), with 2-year event-free survival (EFS) rates of 92% versus 61%, respectively. Similar benefit was observed in the broader stage IB–IIIA population, where 2-year EFS reached 94% with selpercatinib compared with 70% with placebo. Importantly, all three deaths during the study period occurred in the placebo arm.

Long-Term Outcomes Reinforce the Value of Precision Oncology

Few studies better illustrate the impact of precision medicine on NSCLC than the updated results from CROWN. Seven-year follow-up data demonstrated durability with frontline lorlatinib in ALK-positive NSCLC, with 7-year progression-free survival (PFS) rates of 55% compared with 3% for crizotinib (HR, 0.19).² These findings continue to support lorlatinib as a preferred frontline option for ALK-positive disease and underscore how dramatically outcomes have improved in biomarker-selected populations. Long-term success depends on proactive management of treatment-related toxicities, including hyperlipidemia and cognitive effects, allowing patients to remain on therapy and derive maximal benefit.

Expanding Options Beyond Traditional Immunotherapy

HARMONi-6 emerged as one of the most closely watched trials in metastatic squamous NSCLC, demonstrating a significant overall survival (OS) benefit with ivonescimab, a dual PD-1/VEGF-targeting bispecific antibody, plus chemotherapy compared with tislelizumab plus chemotherapy.³ Median OS improved from 23.7 months to 27.9 months (HR, 0.66), supporting ivonescimab-based therapy as a promising new first-line option in advanced squamous NSCLC.

Additional studies explored whether intensified immunotherapy strategies improve outcomes in molecular subsets that historically derive less benefit from standard checkpoint inhibition. The phase 2b TRITON study evaluated the addition of tremelimumab, an anti–CTLA-4 antibody, to durvalumab plus chemotherapy compared with pembrolizumab plus chemotherapy in patients with metastatic non-squamous NSCLC harboring STK11, KEAP1, and/or KRAS mutations. These alterations are associated with an immunologically “cold” tumor microenvironment and poorer outcomes with conventional PD-(L)1–based therapy. Interim results demonstrated numerically higher response rates with the tremelimumab-containing regimen (39% vs 35%), while duration of response was notably prolonged.⁴ These findings suggest that dual checkpoint blockade may help overcome resistance mechanisms in traditionally difficult-to-treat molecular subsets.

Progress Continues in Small Cell Lung Cancer

Recent advances continue to improve outcomes in SCLC, a disease that has historically seen far fewer therapeutic breakthroughs than NSCLC. The phase 3 ADRIATIC trial established consolidation durvalumab following concurrent chemoradiation as a new standard of care for patients with limited-stage disease, demonstrating substantial improvements in both OS and PFS. More recent analyses have shown consistent benefit across key clinical subgroups, further reinforcing the role of durvalumab in this setting.⁵

In extensive-stage SCLC, the phase 3 IMforte study explored whether outcomes could be improved by intensifying maintenance therapy after induction chemoimmunotherapy. Patients received maintenance atezolizumab alone or in combination with lurbinectedin, an FDA-approved agent for relapsed SCLC. The addition of lurbinectedin significantly improved PFS (HR, 0.54) and, more importantly, translated into an OS benefit (HR, 0.73).⁶ These findings are particularly notable in SCLC, where many patients experience rapid clinical deterioration at progression and never receive subsequent therapy. By moving an active drug earlier in the disease course, IMforte supports a proactive maintenance strategy.

Tarlatamab continues to build momentum in SCLC. In the phase 3 DeLLphi-304 study, the DLL3-directed bispecific T-cell engager improved both PFS and OS compared with chemotherapy in patients with relapsed disease. Updated analyses presented at ASCO 2026 also demonstrated improved intracranial activity, with longer central nervous system PFS compared with chemotherapy (6.5 months vs 4.2 months; HR, 0.40).⁷ Ongoing DeLLphi studies will determine whether these benefits can be extended into earlier lines of therapy.

Putting It All Together

The major lung cancer stories from ASCO 2026 highlighted the continued shift toward biomarker-driven care. From adjuvant selpercatinib in RET fusion–positive NSCLC and the durable long-term outcomes seen with lorlatinib, to emerging immunotherapy strategies and evolving treatment approaches in SCLC, advances across the field continue to expand therapeutic options for patients. As targeted therapies move earlier in the disease course and novel agents enter clinical practice, comprehensive molecular testing remains essential to ensuring patients receive the most appropriate treatment.

References

1. Wu Y-L, Hochmair M, Yang Y, et al. Selpercatinib in early-stage RET fusion–positive non–small-cell lung cancer. N Engl J Med. 2026. doi:10.1056/NEJMoa2602628
2. Shaw AT, Solomon BJ, Felip E, et al. Lorlatinib versus crizotinib as first-line treatment for advanced ALK-positive non-small cell lung cancer: 7-year update from the phase 3 CROWN study. Ann Oncol. 2026. doi:10.1016/j.annonc.2026.05.692
3. Chen Z, Yang F, Jiang Z, et al. Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as first-line treatment for advanced squamous non-small-cell lung cancer (HARMONi-6): A randomised, double-blind, phase 3 trial. Lancet. 2025;406(10515):2078-2088. doi:10.1016/S0140-6736(25)01848-3
4. Skoulidis, Ferdinandos, et al. Tremelimumab (T) + durvalumab (D) + chemotherapy (CT) vs pembrolizumab (P) + CT in 1L non-squamous (NSQ) metastatic NSCLC (mNSCLC) with STK11, KEAP1, and/or KRAS mutations (Mut): Interim analysis (IA) of the phase 2b TRITON study.” J Clin Oncol. 2026;44(16):8515. doi:10.1200/JCO.2026.44.16_suppl.8515 
5. Novello S, Spigel DR, Fang J, et al. Patient-reported outcomes with consolidation durvalumab versus placebo after concurrent chemoradiotherapy in limited-stage SCLC: Results from the phase 3 ADRIATIC trial. J Thorac Oncol.2026;21(6):103564. doi:10.1016/j.jtho.2026.103564
6. Paz-Ares LG, Borghaei H, Liu S, et al. Lurbinectedin (lurbi) + atezolizumab (atezo) as first-line (1L) maintenance treatment (Tx) in patients (Pts) with extensive-stage small cell lung cancer (ES-SCLC): Primary results of the phase 3 IMforte trial. J Clin Oncol. 2025;43(16):8006. doi:10.1200/JCO.2025.43.16_suppl.8006
7. Mountzios GS, Chul Cho B, Lammers P, et al. Intracranial efficacy of tarlatamab versus chemotherapy (CTx) as second-line (2L) treatment for small cell lung cancer (SCLC): DeLLphi-304 phase 3 post hoc analysis. J Clin Oncol. 2026;44(16):8006. doi:10.1200/JCO.2026.44.16_suppl.8006