WCLC 2025: The Top 5 Takeaways Across Lung Cancer Care

Treatment with datopotamab deruxtecan-dlnk (dato-DXd; Datroway) demonstrated intracranial activity among those with advanced or metastatic NSCLC harboring brain metastases, as seen in a post hoc analysis of the phase 3 TROPION-Lung01 trial (NCT04656652).

As part of the IASLC 2025 World Conference on Lung Cancer (WCLC), experts from around the world convened in Barcelona, Spain, to exhibit updated findings in lung cancer therapy. Presenters and researchers shared data reflecting how novel approaches in immunotherapy, chemotherapy, and radiation may advance the care of those with non–small cell lung cancer (NSCLC), SCLC, and other lung malignancies.

CancerNetwork^® covered the newest clinical trial findings that researchers presented at the meeting. Here are the top 5 takeaways that may impact lung cancer management.

#1: Dato-DXd Increases Intracranial Responses/PFS in NSCLC With Brain Mets

Treatment with datopotamab deruxtecan-dlnk (dato-DXd; Datroway) demonstrated intracranial activity among those with advanced or metastatic NSCLC harboring brain metastases, as seen in a post hoc analysis of the phase 3 TROPION-Lung01 trial (NCT04656652).¹

Data showed a median central nervous system (CNS) progression-free survival (PFS) of 5.0 months (95% CI, 3.5-not estimable [NE]) in patients who received dato-DXd (n = 38) vs 3.0 months (95% CI, 1.3-6.6) among those who received docetaxel (n = 30; HR, 0.48; 95% CI, 0.23-0.98). In each respective arm, the CNS PFS rates were 77% vs 48% at 3 months and 41% vs 29% at 6 months.

Lead study author Elvire Pons-Tostivint, MD, PhD, from the Department of Medical Oncology at the University Hospital of Nantes in France, and coauthors noted that the intracranial activity associated with dato-DXd in those with metastatic or advanced NSCLC harboring brain metastases was “consistent with previous studies of DXd antibody-drug conjugates in multiple solid tumors.”

#2: Concurrent Durvalumab Plus Chemo/RT Does Not Improve Efficacy in Stage III NSCLC

In the phase 3 EA5181 trial, combining concomitant durvalumab (Imfinzi) with chemotherapy and radiation did not improve efficacy vs chemoradiotherapy alone among patients with stage II unresectable NSCLC.²

The median overall survival (OS) was 41.5 months (95% CI, 34.4-not reached [NR]) in the durvalumab arm vs 39.4 months (95% CI, 33.4-NR) in the chemoradiotherapy alone arm (HR, 1.03; 95% CI, 0.80-1.32; P = .83). Additionally, the median PFS was 15.5 months (95% CI, 13.9-22.1) and 16.4 months (95% CI, 12.0-20.2) in each arm (HR, 1.05; 95% CI, 0.86-1.29; P = .65).

Although combining durvalumab with chemoradiotherapy did not improve OS or PFS and showed no changes in response rates or recurrence patterns, presenting author John M. Varlotto, MD, professor and chief of Radiation Oncology at Marshall Health, noted that the experimental regimen “did not increase toxicity.”

#3: Perioperative Pembrolizumab Combo Improves Responses in NSCLC Subgroups

Based on subgroup data from the phase 3 KEYNOTE-671 trial (NCT03425643), neoadjuvant pembrolizumab (Keytruda) plus chemotherapy before surgery and adjuvant pembrolizumab improved response and survival outcomes among those with early-stage resectable NSCLC regardless of clinical nodal status.³

Data showed that the pembrolizumab regimen improved the major pathological response (mPR) rate and the pathologic complete response (pCR) rate vs placebo/chemotherapy regardless of whether patients had node-negative or node-positive disease. Additionally, the experimental regimen prolonged event-free survival (EFS) among patients with node-negative disease (HR, 0.56; 95% CI, 0.40-0.77), which included those with stage II (HR, 0.56; 95% CI, 0.35-0.68) and stage III disease (HR, 0.49; 95% CI, 0.31-0.60). Pembrolizumab-based therapy also extended an EFS benefit to those with node-positive status (HR, 0.57; 95% CI, 0.45-0.72) in both stage II (HR, 0.39; 95% CI, 0.19-0.82) and stage III subgroups (HR, 0.59; 95% CI, 0.47-0.76).

According to presenting author Heather Wakelee, MD, a medical oncologist and Winston Chen and Phyllis Huang Professor at Stanford Medicine Healthcare, efficacy and safety data from this updated analysis were “consistent with the overall KEYNOTE-671 population after 4 years of follow-up,” thereby supporting “the use of perioperative pembrolizumab in patients with stage II and III [NSCLC] regardless of clinical nodal status.”

#4: Osimertinib Combo Exhibits OS Improvement in EGFR-Mutated Advanced NSCLC

Reports from the phase 3 FLAURA2 trial (NCT04035486)showed that osimertinib (Tagrisso) in combination with chemotherapy significantly and meaningfully extended OS compared with osimertinib monotherapy in those with advanced NSCLC harboring EGFR mutations.⁴

Osimertinib/chemotherapy produced a median OS of 47.5 months (95% CI, 41.0-not calculable) vs 37.6 months (95% CI, 33.2-43.2) with osimertinib alone; an OS benefit with the combination therapy occurred across predefined subgroups (HR, 0.77; 95% CI, 0.61-0.96; P = .02). In each respective arm, the OS rates were 80% vs 72% at 24 months, 63% vs 51% at 36 months, and 49% vs 41% at 48 months.

Presenting author David Planchard, MD, PhD, of the Department of Medical Oncology at the Institut Gustave Roussy, in Villejuif, France, and Faculty of Medicine at Université Paris-Saclay, in Paris, France, stated that these “compelling OS results” affirm osimertinib/chemotherapy as a “first-line standard-of-care treatment in EGFR-mutated advanced NSCLC.”

#5: Adjuvant Nivolumab/Chemo Reduces Recurrence Risk in Resected NSCLC

As demonstrated in the phase 3 NADIM ADJUVANT trial (NCT04564157), combining nivolumab (Opdivo) with chemotherapy meaningfully reduced relapse rates vs chemotherapy alone among patients with resected stage IB to IIIA NSCLC.⁵

In the nivolumab/chemotherapy and chemotherapy alone arms, respectively, the disease-free survival (DFS) rates were 77.7% vs 67.9% at 24 months and 73.3% vs 59.9% at 36 months; the 3-year HR at 57% data maturity was 0.65 (95% CI, 0.40-1.07; P = .085). A sensitivity analysis for cancer-specific DFS showed that the experimental combination maintained a DFS benefit (HR, 0.54; 95% CI, 0.32-0.93; P = .025).

Presenting author Mariano Povencio, MD, chief of the Medical Oncology Department at the Hospital Universitario Puerta de Hierro Majadahonda, noted that despite the immaturity of the results, nivolumab/chemotherapy showed a “meaningful reduction in relapse” and that the “tolerability and safety [of nivolumab/chemotherapy] were consistent with previous data of this treatment from other clinical situations.”

References

1. Pons-Tostivint E, Okamoto I, Ahn MJ, et al. Intracranial efficacy of datopotamab deruxtecan (Dato-DXd) in patients with advanced/metastatic NSCLC in TROPION-Lung01. Presented at the IASLC 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract OA10.01.
2. Varlotto JM, Xie Y, Pennell N, et al. ECOG-ACRIN EA5181: phase 3 trial of concurrent and consolidative durvalumab vs consolidation durvalumab alone for unresectable stage III NSCLC. Presented at the IASLC 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract PL-3.04.
3. Wakelee HA, Demedts I, Langleben A, et al. Perioperative pembrolizumab in non-small cell cancer (NSCLC): 4-Year outcomes by nodal status in the KEYNOTE-671 study. Presented at the IASLC 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract MA04.04.
4. Planchard D, Jänne PA, Kobayashi K, et al. First-line osimertinib + chemotherapy versus osimertinib monotherapy in EGFRm advanced NSCLC: FLAURA2 final overall survival. Presented at the IASLC 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract 1956.
5. Provencio M, Bernabé R, Nadal E, et al. A phase III clinical trial of adjuvant chemotherapy vs chemo-immunotherapy for stage IB-IIIA completely resected non-small cell lung cancer (NSCLC) patients: first interim analysis. Presented at the IASLC 2025 World Conference on Lung Cance;. September 6-9, 2025. Barcelona, Spain. Abstract PL03.07.