Phase 3 Trial Results Do Not Support PORT in Resected Stage IIIAN2 NSCLC

Cecile Le Péchoux, MD

Patients with completely resected stage IIIAN2 non–small cell lung cancer (NSCLC) should not be recommended for post-operative radiotherapy (PORT), according to results from the phase 3 LungART trial (NCT00410683) that were presented during the ESMO Virtual Congress 2020, due to nonstatistically significant increase in disease-free survival (DFS) versus those treated in the control group.

Results showed that the median DFS in the control arm where patients did not receive PORT was 22.8 months (95% CI, 17-37) versus 30.5 months (95% CI, 24-49) in those who received PORT (HR, 0.85; 95% CI, 0.67-1.07; P = .016). The 3-year DFS rates were estimated to be 43.8% (95% CI, 37-51) in the control arm versus 47.1% in the PORT arm (95% CI, 40-54).

A total of 152 DFS events occurred in the control arm, while 144 events were reported in the PORT arm. Mediastinal relapse occurred in 46.1% of patients in the control cohort (n = 70) versus 25.0% of patients in the PORT cohort (n = 36). Additionally, 17.8% of those in the control arm had brain metastases (n = 27), and 46.7% had other metastases (n = 71). In the PORT cohort 23.6% of patients (n = 34) had brain metastases and 49.3% experienced other metastases (n = 71).

Overall survival (OS) rates at 3 years were 68.5% (95% CI, 61-75) in the control arm and 66.5% (95% CI, 59-73) in the PORT arm. Death was reported in 5.3% of patients in the control arm (n = 8) compared with 14.6% of those in the PORT arm (n = 21).

“The differences in [3-year DFS] were not statistically significant,” lead author of the study Cecile Le Péchoux, MD, of the Institut de Cancérologie Gustave Roussy, said during the press conference. She also added, “Regarding the OS curve, there is really no difference between the [arms], but these are very good results in terms of outcome, since these patients are at high risk. More than two-thirds of these patients are living at 3 years; this is also due to the modalities of treatment on relapse that have come out over the past few years.”

The trial enrolled 500 patients with completely resected NSCLC with N2 histology and cytologically-proven nodal involvement. Patients were randomized 1:1 to either the control arm or the PORT arm, where they received 54 gy/5 for 5 weeks. Patients were stratified based on the administration of chemotherapy histology, extent of mediastinal lymph node involvement, and the use of pre-treatment PET scans. The primary end point of the trial was DFS, and key secondary end points included OS, patterns of relapse, local failure, second cancers, and treatment-related toxicity.

Three months after undergoing randomization, 15.0% of patients in the control arm (n = 37) and 23.7% of patients in the PORT arm (n = 57) experienced at least 1 grade 3 or 4 toxicity. At least 1 early grade 3 or 4 toxicity occurred in 7.7% of those in the control group (n = 19) and 8.9% experienced at least 1 late grade 3 or 4 toxicity (n = 22). In the PORT cohort, 11.6% (n = 28) experienced at least 1 early grade 3 or 4 toxicity and 14.6% (n = 36) had at least 1 late grade 3 or 4 toxicity.

While no patients in the control group experienced early grade 5 toxicities, 1.2% (n = 3) of those in the PORT cohort did. These toxicities included cardiopulmonary arrest, pneumonitis, and infectious pneumonitis. Late grade 5 toxicities additionally occurred in 0.8% (n = 2) of those in the control arm, and included depression and respiratory failure. Late grade 5 toxicity was reported in 1.2% (n = 3) of those in the PORT arm and included acute pulmonary edema, respiratory failure. Once unspecified death was reported in the investigational arm.

“The use of PORT was associated with a 15% increase in DFS that was determined to be nonstatistically significant, with no difference in 3-year overall survival; it was also associated with more toxicities that need to be explored further, especially cardiopulmonary events,” Le Péchoux concluded. “At the moment, conform PORT cannot be recommended as a standard of care in all patients who have been completely resected and were stage III and II.

Investigators plan to further analyze patterns of failure, predictive factors of efficacy and toxicity, radiotherapy quality, and surgery quality.

Rafal Dziadziuszko, MD, PhD, of Medical University of Gdansk, commented on the LungART trial during the press conference.

“It has been over 20 years that [thoracic oncologists] have been debating on the issue as to whether or not [radiation should be used on] patients with mediastinal lymph node involvement after surgery.” Dziadziuszko said. He went on to say, “Physicians around the world hesitated whether to provide this service for patients or not. The arguments in favor were that you can increase local control…. The arguments against were that we did not have significant evidence that this treatment prolonged survival. There is also an argument of potential harm.”

_Reference

_{Le Péchoux C, Pourel N, Barlesi F, et al. An international randomized trial, comparing post-operative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non-small cell lung cancer (NSCLC) and mediastinal N2 involvement. Primary end-point analysis of Lung ART (IFCT-0503, UK NCRI, SAKK) NCT00410683. Presented at: 2020 ESMO Virtual Meeting; September 19-21, 2020; Virtual. Abstract: LBA3_PR.}