乌鸦传媒

Almost a fourth of patients with newly diagnosed advanced PD-L1-positive non-small cell lung cancer (NSCLC) lived 5 years or longer when treated with the immune checkpoint inhibitor pembrolizumab (Keytruda), long-term follow-up from a phase I trial showed.

Patients who received pembrolizumab as initial therapy had an estimated 5-year overall survival (OS) of 23.2%, whereas those with previously treated NSCLC had an estimated 5-year OS of 15.5%. Five-year estimated OS increased to almost 30% in the subgroup of patients with high PD-L1 expression and no prior treatment for advanced NSCLC, reported Edward B. Garon, MD, of the University of California Los Angeles, and colleagues.

The numbers reflect the progress that has occurred in a relatively short period of time, as patients with metastatic NSCLC had a 5-year OS of 5.5% , they wrote in the .

"Five-year outcomes from the study demonstrate that pembrolizumab provides long-term OS benefit and durable responses with tolerable safety for treatment-naive and previously treated patients with advanced PD-L1-expressing NSCLC," the investigators wrote. "In the context of low historical 5-year survival in advanced NSCLC, these data demonstrate the potential of pembrolizumab treatment to improve long-term outcomes for patients with advanced NSCLC."

Early success with immunotherapy and targeted agents stimulated great optimism about the potential to improve outcomes in advanced NSCLC, authors of an noted. However, amid decades of "frustratingly small advances," questions persisted about the impact of the new therapies on long-term outcomes of "this hitherto recalcitrant disease," wrote Deepa Rangachari, MD, and Daniel B. Costa, MD, PhD, both of Beth Israel Deaconess Medical Center in Boston. Long-term results from provided provided additional reason for optimism.

"Given the progress made in the past decade, it is not unrealistic to think that with future decades, the dismal survival rates for all stages of lung cancer can be meaningfully -- and durably -- improved beyond what has already been achieved in studies like KEYNOTE-001," Rangachari and Costa concluded.

Early Success with Immunotherapy

The introduction of anti-PD-1/L1 immunotherapeutic agents represented a major advance in the treatment of NSCLC. The KEYNOTE-001 trial was the to demonstrate pembrolizumab's antitumor activity and acceptable toxicity in advanced NSCLC, which included patients with previously treated and untreated disease, Garon and colleagues noted.

In KEYNOTE-001, patients with a PD-L1 tumor proportion score (TPS) ≥50% had a higher response rate and better OS, as compared with patients who had lower or absent PD-L1 expression. A showed that pembrolizumab improved OS versus chemotherapy in patients with previously treated advanced NSCLC and TPS ≥1%. In the first-line setting, pembrolizumab improved OS versus chemotherapy in patients with and .

Garon and colleagues reported survival data from long-term follow-up in KEYNOTE-001, which has accumulated the longest follow-up to date for patients with advanced NSCLC treated with pembrolizumab monotherapy.

Eligible patients had locally advanced or metastatic NSCLC, measurable disease, and ECOG performance status 0-1. Investigators enrolled patients to two cohorts: untreated and previously treated. Untreated patients had no prior systemic therapy for advanced disease or adjuvant therapy within the previous year, no EGFR or ALK ≥1%. Previously treated patients had received one or more prior systemic therapies for advanced disease and had no evidence of active central nervous system disease.

Treatment with pembrolizumab continued until disease progression, and the trial had a primary endpoint of objective response rate. OS and duration of response were key secondary endpoints.

Data analysis included 550 patients, 101 with previously untreated disease and 449 with previously treated NSCLC. The primary analysis showed that 41.6% of patients with previously untreated NSCLC achieved objective responses with pembrolizumab, as did 22.9% of patients in the previously treated cohort. Three untreated patients and five previously treated patients had complete responses. Median duration of response was 16.8 months in the untreated group and 38.9 months in patients with previously treated NSCLC.

Durable Responses, Better Long-Term OS

Median OS was 22.3 months for patients with untreated disease and 10.5 months for previously treated patients. In addition to the 5-year OS, landmark analyses for patients with untreated disease revealed 2-year OS of 49.0%, 3-year OS of 37.0%, and 4-year OS of 31.0%. Among patients with previously treated NSCLC, OS was 30.1%, 20.9%, and 18.2% at 2, 3, and 4 years, respectively.

Previously untreated patients with TPS ≥50% had a median OS of 35.4 months, in addition to 5-year OS of 29.6%. Those with TPS 1-49% had a median OS of 19.5 months and 5-year OS of 15.7%. Among previously treated patients with TPS ≥50%, median OS was 15.4 months, and 5-year OS was 25.0%, as compared with 8.5 months and 12.6% for patients with TPS 1-49%. The TPS <1% subgroup had a median OS of 8.6% and 5-year OS of 3.5%.

With regard to safety, treatment-related adverse events (TRAEs) occurred in 70% of 550 patients, and grade 3-5 TRAEs occurred in 13% of patients. Three grade 3-5 TRAEs occurred after 3 years.

"The durability of responses achieved during pembrolizumab appeared to be an important contributor to the OS outcomes," Garon and colleagues wrote. "A subgroup of patients were not only alive at 5 years but also achieved durable responses, with some patients in both the treatment-naive and previously treated groups having response durations of 4 years or more."