ESMO 2026: ADCs and New Combinations Advance Lung Cancer Care

Antibody-drug conjugates (ADCs) were prominent among trials presented at the 2026 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain. The findings in lung cancer included phase 3 trials that reported benefit over chemotherapy-based regimens in non–small cell lung cancer (NSCLC). Other presentations revisited the role of chemotherapy alongside pembrolizumab (Keytruda) in PD-L1–high disease and offered early data on a bispecific antibody after progression on chemoimmunotherapy, showing that more selective and tolerable therapies are on the way in NSCLC.

Sac-TMT Plus Pembrolizumab Extends PFS in PD-L1–Negative Nonsquamous NSCLC

First-line use of the TROP2-targeted ADC sacituzumab tirumotecan (sac-TMT) plus pembrolizumab more than doubled median progression-free survival (PFS) compared with chemotherapy plus pembrolizumab in patients with PD-L1–negative advanced nonsquamous NSCLC, according to findings from the phase 3 OptiTROP-Lung06 trial (NCT06711900) that were published simultaneously in The New England Journal of Medicine.^1,2

Among 455 untreated patients with stage IIIB to IV disease at a median follow-up of 9.7 months, median PFS by blinded independent central review was 15.0 months (95% CI, 9.9-not estimable) with sac-TMT plus pembrolizumab vs 5.7 months (95% CI, 5.5-7.4) with chemotherapy plus pembrolizumab (HR, 0.49; 95% CI, 0.36-0.65; P < .001). The 12-month PFS rates were 51.1% vs 22.8%, respectively.

Objective response rates (ORRs) were similar in the 2 arms (50.2% vs 47.3%). However, deep responses were more frequent with sac-TMT (28.8% vs 17.3%), and median duration of response was longer (13.6 vs 6.8 months; HR, 0.47). Overall survival (OS) data were immature at the first interim analysis and were analyzed descriptively only (HR, 0.58; 95% CI, 0.38-0.88).

Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 47.6% of patients in the sac-TMT arm vs 60.6% in the chemotherapy arm. TEAEs led to dose reductions in 4.8% vs 19.9% of patients. Stomatitis occurred in 51.1% of patients receiving sac-TMT, and 2.2% of cases were grade 3.

Sac-TMT Extends OS in EGFR-Mutated NSCLC After TKI Progression

In a separate study, the phase 3 OptiTROP-Lung04 trial (NCT05870319), Sac-TMT extended OS compared with platinum-based chemotherapy in patients with EGFR-mutated nonsquamous NSCLC whose disease progressed on EGFR tyrosine kinase inhibitor (TKI) therapy.³

In the final OS analysis with median follow-up of 32.3 months, the median OS was 25.9 months (95% CI, 22.2-27.5) with sac-TMT vs 17.4 months (95% CI, 15.7-20.3) with chemotherapy (HR, 0.69; 95% CI, 0.54-0.89; nominal 1-sided P = .002). The 24-month OS rates were 54.1% vs 37.2%, respectively.

In the open-label trial, 376 patients were randomly assigned to sac-TMT 5 mg/kg every 2 weeks or to pemetrexed plus carboplatin or cisplatin, followed by pemetrexed maintenance. Eligible patients had progressed after a third-generation EGFR TKI, or after a first- or second-generation TKI with T790M-negative disease. PFS by blinded independent central review, the primary end point, was previously reported in The New England Journal of Medicine (median, 8.3 vs 4.3 months; HR, 0.49).⁴

More patients in the chemotherapy arm went on to receive a subsequent ADC (22.6% vs 3.5%). In a prespecified rank-preserving structural failure time analysis that adjusted for later ADC use, the OS HR was 0.57 (95% CI, 0.42-0.75).

Grade 3 or higher treatment-related AEs (TRAEs) occurred in 58.5% vs 53.8% of patients, respectively. Serious TRAEs occurred in 10.1% vs 18.1% in the respective arms. No patient in the sac-TMT arm discontinued treatment because of a TRAE. Grade 3 stomatitis occurred in 4.8% of patients receiving sac-TMT, and interstitial lung disease or pneumonitis occurred in 1 patient.

Adding Chemotherapy to Pembrolizumab Extends PFS in PD-L1–High NSCLC

Adding platinum-based chemotherapy to first-line pembrolizumab more than doubled median PFS compared with pembrolizumab alone in patients with advanced NSCLC and PD-L1 expression of 50% or higher, according to results from the open-label phase 3 PERSEE trial (NCT04547504).⁵

At a median follow-up of 38.7 months among 321 randomly assigned patients, median PFS by blinded central review was 16.1 months (95% CI, 11.0-34.1) with pembrolizumab plus chemotherapy vs 6.9 months (95% CI, 5.5-9.3) with pembrolizumab monotherapy (HR, 0.56; 95% CI, 0.43-0.74; P < .001. The 36-month PFS rates were 39.2% vs 20.8%, respectively. The combination resulted in a higher ORR (77.5% vs 50.3%) and less early progression (5.8% vs 26.5%). Median OS was 50.2 vs 29.9 months (HR, 0.77; 95% CI, 0.56-1.05), although the trial was not powered to detect an OS difference.

Grade 3 or higher TRAEs occurred in 54% vs 19% of patients and were largely attributed to chemotherapy. In the combination arm, 48% of patients discontinued chemotherapy because of adverse events.

Iza-Bren Nearly Doubles PFS in EGFR-Mutated NSCLC After Third-Generation TKI

Izalontamab brengitecan (iza-bren), a bispecific ADC targeting EGFR and HER3, nearly doubled median PFS compared with platinum-based chemotherapy. The open-label trial enrolled patients with EGFR-mutated nonsquamous NSCLC whose disease progressed on a third-generation EGFR TKI. The interim results from the phase 3 PANKU-Lung01 trial (NCT06382116) were published in The Lancet.^6,7

The trial randomly assigned 432 patients median PFS by blinded independent central review was 11.1 months (95% CI, 9.2-12.7) with iza-bren vs 5.7 months (95% CI, 5.5-5.9) with chemotherapy (HR, 0.40; 95% CI, 0.31-0.51; 1-sided P < .001). The 12-month PFS rates were 46.5% vs 14.4%, respectively. The confirmed ORR was 60.2% vs 34.5%, and median duration of response was 10.4 vs 5.7 months, respectively.

More patients in the chemotherapy arm went on to receive an ADC (29.1% vs 2.8%). Although OS was immature, median OS was not reached in the iza-bren arm vs 19.4 months in the chemotherapy arm, and 18-month OS rates were 68.8% vs 55.3%.

Grade 3 or higher TRAEs occurred in 78.7% vs 62.1% of patients, mainly hematologic. TRAEs led to dose reductions in 60.2% vs 23.3% of patients but led to discontinuation in only 1.9% of each arm. Treatment-related interstitial lung disease occurred in 2 patients (0.9%) receiving iza-bren.

Pumitamig Plus Docetaxel Shows Early Activity After Chemoimmunotherapy

Pumitamig (BNT327), a bispecific antibody targeting PD-L1 and VEGF-A, was combined with docetaxel in patients with metastatic NSCLC that progressed on first-line chemoimmunotherapy in the global, open-label ROSETTA Lung-107 trial (NCT06841055).⁸

Among 30 response-evaluable patients, the confirmed ORR was 36.7% (95% CI, 19.9%-56.1%) and the disease control rate was 90.0%. Confirmed responses occurred in 42.9% of patients with a PD-L1 tumor proportion score below 1% and in 57.1% of patients with squamous histology. Median PFS was 6.9 months (95% CI, 4.2-not reached) at a median follow-up of 12.2 weeks.

Among 50 treated patients, grade 3 or higher TRAEs occurred in 18%, and 8% discontinued treatment because of TRAEs. Bleeding events occurred in 16% of patients, all grade 1. Grade 3 or higher immune-related adverse events occurred in 10%, including grade 4 colitis and grade 4 pneumonitis in 1 patient each.

REFERENCES

1. Zhou C, Zhou F, Meng X, et al. Sacituzumab tirumotecan (sac-TMT) plus pembrolizumab (P) versus chemotherapy (chemo) plus pembrolizumab (P) as first-line (1L) treatment for PD-L1-negative advanced non-squamous (nsq) NSCLC: Randomized phase 3 OptiTROP-Lung06 study. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA66.

2. Zhou F, Meng X, Ding Q, et al. Sacituzumab tirumotecan plus pembrolizumab in PD-L1-negative advanced NSCLC. N Engl J Med. Published online October 25, 2026. doi:10.1056/NEJMoa2611280

3. Zhang L, Fang WF, Wu L, et al. Final OS analysis of sacituzumab tirumotecan (sac-TMT) versus platinum-based chemotherapy in EGFR-mutated non-small cell lung cancer (NSCLC) after progression on EGFR-TKI: Phase III OptiTROP-Lung04 study. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA67.

4. Fang W, Wu L, Meng X, et al. Sacituzumab tirumotecan in EGFR-TKI-resistant, EGFR-mutated advanced NSCLC. N Engl J Med. 2026;394(1):13-26. doi:10.1056/NEJMoa2512071

5.Decroisette C, Descourt R, Bernardi M, et al. Pembrolizumab with or without platinum-based chemotherapy as first-line treatment in advanced NSCLC with PD-L1 ≥50%: PERSEE phase 3 trial (GFPC 01-2020). Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract 2614O.

6. Zhang L, Yang Y, Meng X, et al. PANKU-Lung01: randomized phase III study of izalontamab brengitecan (iza-bren) vs platinum-based chemotherapy (PBC) in patients with EGFR-mutant non-squamous non-small cell lung cancer (NSCLC) after progression on a third-generation EGFR tyrosine kinase inhibitor (TKI). Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA71.

7. Hong S, Zhou T, Hou X, et al. Izalontamab brengitecan versus platinum-based chemotherapy in EGFR-mutated advanced non-squamous non-small-cell lung cancer after progression on third-generation EGFR tyrosine kinase inhibitors (PANKU-Lung01): a multicentre, randomised, open-label, phase 3 trial in China. Lancet. Published online October 2026. doi:10.1016/S0140-6736(26)02026-X

8. Cho BC, Williams A, Ozyilkan O, et al. A global phase 2, open-label trial of pumitamig (PD-L1 × VEGF-A bsAb) + docetaxel post-chemoimmunotherapy in mNSCLC: first data from ROSETTA Lung-107. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA76.