ASCO 2026 Lung Cancer Data Highlight Advances Across Targeted Agents and Immunotherapy

The 2026 ASCO Annual Meeting will feature a robust collection of data advancing the treatment of patients with non–small cell lung cancer (NSCLC) across multiple settings and mutation types. Six abstracts released ahead of the meeting collectively paint a picture of a rapidly evolving treatment landscape.

Be sure to follow our complete coverage of these studies and the most significant abstracts across all tumor types during our full coverage of the 2026 ASCO Annual Meeting.

Amivantamab Plus Lazertinib Achieves Nearly 3.5-Year Median OS in Atypical EGFR-Mutated NSCLC

Patients with atypical EGFR-mutated advanced NSCLC have historically faced inferior outcomes compared with those harboring classical mutations. Updated data from Cohort C of the phase 1/Ib CHRYSALIS-2 study (NCT04077463) now demonstrate a median OS of 41.0 months (95% CI, 27.7-not estimable) with first-line amivantamab plus lazertinib (ami-laz) in 49 treatment-naive patients with atypical EGFR mutations, excluding exon 20 insertions and co-mutations with classical EGFR.¹

At a median follow-up of 31.3 months 55% of patients were alive at 3 years and 46% at 4 years. Twenty percent of patients (10/49) remained on first-line treatment at the time of data cutoff, with a duration range of 2.5 to 4.4 years, and 7 patients had received amivantamab for more than 3 years. Among patients who progressed and discontinued first-line therapy, 71% (20/28) received subsequent treatment, most commonly platinum-based chemotherapy (55%).

The safety profile was consistent with prior CHRYSALIS-2 reports, with no new signals identified with longer follow-up. These data add to the growing body of evidence supporting ami-laz across EGFR-mutated settings, following the phase 3 MARIPOSA trial demonstration of significant OS benefit over osimertinib in classical EGFR-mutated disease (HR, 0.75; P =.005).

Pumitamig Combo Achieves 70% ORR in First-Line NSCLC, Regardless of PD-L1 Status

Pumitamig (BNT327/BMS986545), a novel investigational bispecific antibody targeting both PD-L1 and VEGF-A, demonstrated an overall response rate (ORR) of 70.0% and a disease control rate of 100% in the phase 2 dose-optimization portion of the global ROSETTA Lung-02 trial (NCT06712316) in treatment-naive advanced NSCLC.²

The phase 2 portion enrolled 44 patients with no actionable genomic alterations and ECOG PS of 0 or 1, randomized 1:1 to pumitamig at 1400 mg (DL1) or 2000 mg (DL2) combined with histology-specific chemotherapy every 3 weeks. Among 40 response-evaluable patients, the confirmed ORR was 52.5% (21/40), with 5 responses pending confirmation at the November 21, 2025, data cutoff. Median best tumor volume change was -38.2% overall (-36.6% non-squamous; -39.7% squamous). Activity was observed regardless of PD-L1 expression level, including in 20 patients with PD-L1 below 1%. The lower dose (DL1) produced particularly encouraging ORRs of 72.7% in non-squamous and 81.8% in squamous NSCLC. Median treatment duration was 4.5 months, with 69.8% of patients still on treatment at data cutoff.

Treatment-emergent adverse events (TRAEs) occurred in 93.0% of patients, with grade 3 or higher TRAEs in 44.2% and pumitamig-related grade 3 or higher TRAEs in 18.6%. Immune-related AEs occurred in 14.0% of patients, with grade 3 or higher in 2.3%. Bleeding events were reported in 16.3% of patients, with only one grade 3 event. Treatment discontinuation due to pumitamig-related TRAEs occurred in 4.7% of patients. Based on the encouraging efficacy at the lower dose, DL1 is now being evaluated versus pembrolizumab plus chemotherapy in the ongoing phase 3 portion of the trial.

Silevertinib Hits High Response and Intracranial Response Rates in Treatment-Naive EGFR+ NSCLC

Silevertinib (BDTX-1535), a fourth-generation covalent EGFR TKI with high CNS penetrance, demonstrated robust anti-tumor activity in 43 treatment-naive patients with advanced EGFR non-classical mutation (NCM) NSCLC enrolled in cohort 3 of its phase 2 trial (NCT05256290). The population included 35 unique non-classical mutation types, 25 patients with PACC mutations, and 16 with compound mutations (≥2 non-classical mutations). Median age was 70.0 years, 72% were female, 74% were White, and 42% were never-smokers.³

In the intent-to-treat population, the ORR was 60% (26/43; 95% CI, 44.4-75.0) and the DCR was 91% (39/43; 95% CI, 77.9-97.4). In the PACC mutation subgroup, the ORR was 56% (14/25; 95% CI, 34.9-75.6) and DCR was 88% (22/25; 95% CI, 68.8-97.5). In compound mutation patients, the ORR was 69% (11/16; 95% CI, 41.3-89.0) and DCR was 94% (15/16; 95% CI, 69.8-99.8). The 6-month PFS rate was 86% overall and 80% in patients with CNS metastases. Among 7 patients with measurable intracranial disease, the CNS ORR by RANO-BM criteria was 86% (6/7). Complete ctDNA clearance was observed in 81% of evaluable patients (21/26).

Although 77% of patients required dose reduction, 86% of patients with a radiographic response (19/22) maintained or deepened their response afterward, including all patients with CNS responses. Grade 3 TRAEs included rash (19%), diarrhea (19%), stomatitis (9%), and paronychia (5%). Serious TRAEs were reported in 12% of patients, with 9% discontinuing treatment due to TRAEs.

DZD6008 Shows Promise in C797X-Mutated NSCLC

DZD6008 is an investigational fourth-generation EGFR TKI designed to overcome acquired C797X resistance mutations—among the most common mechanisms of progression following third-generation EGFR TKI therapy—with preclinical data demonstrating high selectivity over wild-type EGFR and full blood-brain barrier penetration. Phase 1/2 data from the TIAN-SHAN1 (NCT06905197) and TIAN-SHAN2 (NCT06813365) studies show promising and durable anti-tumor activity in this resistant population.⁴

As of the December 19, 2025, data cutoff, 24 patients with confirmed C797X-positive NSCLC and at least one post-baseline tumor assessment had received once-daily oral DZD6008 at 20 mg (n=1), 40 mg (n=13), or 60 mg (n=10). Median age was 66.5 years, 58.3% were female, 91.7% were Asian, and 58.3% had ECOG PS 1. All patients had metastatic disease and had received a median of 2 prior lines of therapy (range, 1-6). Tumor shrinkage was observed in 75% of patients overall, with an ORR of 41.7% across all dose levels. At the two recommended phase 2 doses, the ORR was 23.1% at 40 mg and 60.0% at 60 mg. Neither the median duration of response nor the median PFS was reached at either dose. The 9-month PFS rate was 54.5% at 40 mg and 64.8% at 60 mg. Intracranial anti-tumor activity was observed in patients with baseline brain metastases.

DZD6008 was well tolerated with no dose-limiting toxicities. Grade 3 or higher TRAEs included decreased lymphocyte count (8.3%) and anemia, malaise, fatigue, and increased amylase (each 4.2%). No grade 5 TRAEs were reported.

Amivantamab Demonstrates Promising Intracranial Activity in Real-World EGFR-Mutated NSCLC

Real-world data from a multi-center retrospective study across 7 centers show that amivantamab-based regimens, used as monotherapy or in combination, produce clinically meaningful intracranial responses in heavily pretreated EGFR-mutated NSCLC patients with brain parenchymal metastases and/or leptomeningeal metastases — a population in which treatment options after third-generation EGFR TKI progression remain severely limited.⁵

The study enrolled 31 patients (13 with brain metastases alone; 18 with combined brain and leptomeningeal disease). Most patients (80.6%; 25/31) harbored sensitizing EGFR mutations and had progressed on third-generation EGFR TKIs, while 6 patients (19.4%) carried atypical EGFR mutations. More than half (54.8%; 17/31) had received 4 or more prior lines of therapy. Amivantamab monotherapy was used in 10 of 31 patients (32.3%).

The median intracranial PFS was 10.3 months (95% CI, 4.5-16.1). Among 24 evaluable patients, the intracranial ORR by RANO-BM and/or RANO-LM criteria was 25.0% (6/24) and the intracranial DCR was 91.7% (22/24). CNS-related symptom improvement was reported in 83.9% of patients (26/31). Exploratory CSF analyses demonstrated decreased CSF pressure and carcinoembryonic antigen levels, reduced EGFR amplification, and clearance of EGFR C797S—a key acquired resistance mutation—suggesting potential activity against third-generation TKI resistance mechanisms in the CNS compartment. These findings support amivantamab as a viable therapeutic option in this challenging population and highlight the emerging utility of CSF biomarkers for monitoring intracranial treatment response.

Sacituzumab Tirumotecan Plus Pembrolizumab Significantly Improves PFS in PD-L1–Positive Advanced NSCLC

Sacituzumab tirumotecan (sac-TMT) combined with pembrolizumab reduced the risk of progression or death by 65% and the risk of death by 45% compared with pembrolizumab alone in patients with treatment-naive, PD-L1-positive advanced NSCLC, according to a planned interim analysis of the phase 3 OptiTROP-Lung05 study (NCT06448312).⁶

The trial enrolled 413 patients with locally advanced or metastatic NSCLC without EGFR or ALK alterations and PD-L1 TPS of 1% or higher, randomized 1:1 to sac-TMT 4 mg/kg every 2 weeks plus pembrolizumab 400 mg every 6 weeks (n=208) or pembrolizumab alone (n=205). Median age was 65 years, 84.5% had ECOG PS 1, 40.0% had squamous histology, and 40.0% had PD-L1 TPS ≥50%.

At a median follow-up of 10.5 months, median PFS was not reached with sac-TMT plus pembrolizumab versus 5.7 months with pembrolizumab alone (HR, 0.35; 95% CI, 0.26-0.47; P <.0001). The ORR was 70.2% versus 42.0%, respectively. OS data were immature but trended favorably for the combination (HR, 0.55; 95% CI, 0.36-0.85).

The PFS benefit was consistent across all prespecified subgroups. In patients with PD-L1 TPS 1%-49%, the HR was 0.28 (95% CI, 0.19-0.41); in those with TPS ≥50%, it was 0.47 (95% CI, 0.29-0.77). In non-squamous patients the HR was 0.28 (95% CI, 0.18-0.43) and in squamous patients 0.44 (95% CI, 0.29-0.66).

Grade 3 or higher TEAEs occurred in 55.3% of combination patients versus 31.4% with pembrolizumab alone. The most common grade 3 or higher TEAEs of special interest for sac-TMT were decreased neutrophil count (17.3%), anemia (9.1%), and stomatitis (5.3%). TEAEs led to discontinuation of sac-TMT in 3.8% of patients, and no new safety signals were identified.

REFERENCES

1. Neal J, et al. Overall survival of first-line amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer (NSCLC): updated results from the CHRYSALIS-2 study. J Clin Oncol. 2026;44(suppl 16):abstr 8501.

2. Peters S, et al. Phase 2 data from ROSETTA Lung-02, a global randomized phase 2/3 trial of pumitamig (PD-L1 × VEGF-A bsAb) + chemotherapy in 1L NSCLC. J Clin Oncol. 2026;44(suppl 16):abstr 8513.

3. Rotow J, et al. Safety and efficacy results of the phase 2 study of silevertinib (BDTX-1535) in treatment-naïve patients with non-small cell lung cancer with non-classical EGFR mutations. J Clin Oncol. 2026;44(suppl 16):abstr 8519.

4. Wang M, et al. DZD6008, a fourth-generation EGFR TKI, in pretreated NSCLC patients with EGFR C797X mutations: results from phase 1/2 studies. J Clin Oncol. 2026;44(suppl 16):abstr 8520.

5. Zhou Q, et al. Amivantamab in EGFR-mutated NSCLC with refractory brain or leptomeningeal metastases: a multi-center real-world study. J Clin Oncol. 2026;44(suppl 16):abstr 8521.

6. Cheng Y, et al. Sacituzumab tirumotecan plus pembrolizumab versus pembrolizumab in first-line PD-L1-positive advanced non-small cell lung cancer: results from the phase 3 OptiTROP-Lung05 study. J Clin Oncol. 2026;44(suppl 16):abstr 8506.