Highlights
The Evolution trial (WJOG11819L) reports a 2-year progression-free survival (PFS) rate of 67% in patients with unresectable, locally advanced non-small-cell lung cancer (NSCLC) and a PD-L1 tumor proportion score (TPS) of 50% or higher using a radiotherapy-free approach.
This strategy utilized pembrolizumab in combination with platinum-based chemotherapy as induction, followed by maintenance pembrolizumab, successfully omitting consolidated radiotherapy.
Safety data showed that while grade 3 or higher adverse events occurred, primarily hematological, no treatment-related deaths were reported, and the incidence of severe pneumonia was manageable at 14%.
The Clinical Burden and Evolution of Stage III NSCLC Treatment
Unresectable, locally advanced (Stage III) non-small-cell lung cancer (NSCLC) represents a heterogeneous and challenging clinical scenario. Traditionally, the gold standard for these patients has been definitive platinum-based concurrent chemoradiotherapy (cCRT). The landscape shifted dramatically following the PACIFIC trial, which established consolidation therapy with the PD-L1 inhibitor durvalumab as the standard of care for patients whose disease had not progressed after cCRT. This regimen significantly improved both progression-free survival and overall survival, setting a high bar for subsequent clinical investigations.
However, the integration of radiotherapy is not without significant drawbacks. Concurrent chemoradiotherapy is associated with substantial toxicities, most notably radiation-induced pneumonitis and esophagitis, which can impair quality of life and limit subsequent treatment options. Furthermore, some patients are ineligible for radiotherapy due to large tumor volumes, interstitial lung disease, or poor pulmonary function. In the era of potent immunotherapy, a critical question has emerged: can patients with high PD-L1 expression achieve similar or better outcomes with intensive systemic therapy alone, thereby avoiding the complications of thoracic radiation? The Evolution trial was designed to address this unmet need, specifically focusing on the subgroup of patients with a PD-L1 tumor proportion score (TPS) of 50% or higher.
Study Design and Methodology: The Evolution Trial (WJOG11819L)
The Evolution trial was a prospective, multicentre, single-arm, phase 2 study conducted across nine specialized institutes in Japan. The study recruited patients aged 20 years or older with histologically confirmed, unresectable, locally advanced NSCLC. Crucially, eligible patients were required to have a PD-L1 TPS of 50% or higher, as determined by the 22C3 pharmDx assay. Other inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion according to RECIST version 1.1, no prior systemic therapy, and preserved organ function.
The Treatment Regimen
The study protocol involved an intensive induction phase followed by a long-term maintenance phase. During induction, patients received intravenous pembrolizumab (200 mg) every three weeks combined with platinum-based chemotherapy for four cycles. The chemotherapy backbone was tailored to histology: patients with non-squamous NSCLC received cisplatin (75 mg/m2) or carboplatin (AUC 5) plus pemetrexed (500 mg/m2); patients with squamous NSCLC received cisplatin or carboplatin (AUC 6) plus nanoparticle albumin-bound (nab)-paclitaxel (100 mg/m2 on days 1, 8, and 15).
Following the induction phase, patients transitioned to maintenance therapy. This consisted of pembrolizumab (200 mg) every three weeks for up to 2 years. For those with non-squamous histology, pemetrexed (500 mg/m2) could be continued alongside pembrolizumab at the investigator’s discretion. The primary endpoint was the 2-year progression-free survival (PFS) rate, a rigorous metric for a phase 2 trial in the locally advanced setting.
Key Findings: Efficacy and Survival Outcomes
Between May 2020 and February 2022, 21 patients were enrolled and treated. The cohort reflected a typical advanced lung cancer population, with a median age of 73 years and a predominance of male patients (76%). Despite the small sample size, the results were striking. After a median follow-up of 32.5 months, the study met its primary objective.
Progression-Free and Overall Survival
The 2-year PFS rate was 67% (90% CI 46–83). This figure is particularly noteworthy when compared to historical benchmarks for chemoradiotherapy followed by durvalumab, where 2-year PFS rates typically hover around 45% to 50% in unselected populations. While cross-trial comparisons are inherently limited, the high PFS rate suggests that in the PD-L1 high population, systemic chemo-immunotherapy alone may provide sufficient local and systemic control.
In terms of treatment completion, 86% of patients (18 of 21) successfully completed the induction phase. Ten patients (48%) completed the full 2-year maintenance course. The reasons for discontinuation during maintenance included disease progression (n=3) and adverse events (n=5).
Safety and Tolerability Profile
A primary concern with omitting radiotherapy is whether the systemic regimen itself poses manageable risks. In the Evolution trial, the safety profile was consistent with the known toxicities of pembrolizumab and platinum-doublet chemotherapy. Grade 3 or worse adverse events occurred in several patients, with the most frequent being neutropenia (38%), leukopenia (19%), and pneumonia (14%).
Serious adverse events (SAEs) were reported in 33% of the cohort. Importantly, there were no treatment-related deaths. The incidence of pneumonia is of particular interest to clinicians; at 14% for grade 3 or higher, it appears comparable to or slightly lower than rates observed in patients undergoing concurrent chemoradiotherapy followed by durvalumab, where the additive risk of radiation-induced and immune-mediated pneumonitis is a constant clinical concern.
Expert Commentary: Mechanistic Insights and Clinical Implications
The Evolution trial provides a provocative proof-of-concept for the radiotherapy-free management of Stage III NSCLC. From a biological perspective, patients with a PD-L1 TPS ≥50% are known to have highly immunogenic tumors that are particularly sensitive to PD-1/PD-L1 blockade. In the metastatic setting (KEYNOTE-024), pembrolizumab monotherapy outperformed chemotherapy in this group. By moving this potent systemic approach into the locally advanced setting and adding chemotherapy—which can enhance neoantigen release and deplete immunosuppressive cells—the Evolution trial investigators hypothesized that radiotherapy might be redundant for some patients.
The Advantage of Omitting Radiotherapy
The potential clinical advantages of a radiotherapy-free approach are manifold. First, it simplifies the treatment journey for the patient, removing the need for daily hospital visits for 6 to 7 weeks of radiation. Second, it preserves pulmonary function by avoiding radiation-induced fibrosis, which is critical for patients who may require subsequent surgical salvage or further lines of systemic therapy. Third, it eliminates the risk of radiation-induced esophagitis and cardiotoxicity.
Limitations and Considerations
Despite the promising results, several caveats remain. This was a single-arm, phase 2 study with a very small sample size (n=21). The results, while statistically encouraging, require validation in larger, randomized phase 3 trials. Additionally, the study was conducted entirely in Japan, and the generalizability to other ethnic groups remains to be confirmed. There is also the question of whether local control is truly equivalent to CRT in the long term; while PFS is high, the pattern of first recurrence (local vs. distant) will be essential data for future analyses.
Conclusion and Summary
The Evolution trial (WJOG11819L) represents a significant step toward personalized medicine in Stage III NSCLC. It demonstrates that for the specific subgroup of patients with PD-L1 TPS ≥50%, a combination of pembrolizumab and chemotherapy without radiotherapy is not only feasible but yields high 2-year survival rates. While chemoradiotherapy followed by durvalumab remains the current standard of care, this radiotherapy-free strategy offers a promising alternative, particularly for patients who are poor candidates for radiation or those seeking to minimize localized toxicities.
Future research should focus on comparing this approach directly against the PACIFIC regimen in a randomized fashion. Until then, the Evolution trial serves as a compelling signal that in the era of advanced immunotherapy, the ‘standard’ may soon become more flexible based on molecular and immunological biomarkers.
Funding and ClinicalTrials.gov
This study was funded by Merck Sharp & Dohme (MSD). The trial is registered with ClinicalTrials.gov under the identifier NCT04153734.
References
Hata A, Ninomaru T, Okada H, Kogure Y, Oki M, Katakami N, Kijima T, Yokoyama T, Matsumoto H, Sato Y, Kato T, Sugawara S, Sawada T, Yoshimura K, Seto T, Nakagawa K, Okamoto I, Yamamoto N; West Japan Oncology Group. Radiotherapy-free pembrolizumab combined with chemotherapy for locally advanced non-small-cell lung cancer with PD-L1 tumour proportion score of 50% or higher (Evolution trial): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2025 Nov;26(11):1432-1442. doi: 10.1016/S1470-2045(25)00462-0. Epub 2025 Oct 11. PMID: 41082893.
