乌鸦传媒

Twice as many patients with advanced lung cancer carrying high PD-L1 expression lived 5 years or longer if they started treatment with pembrolizumab (Keytruda) instead of chemotherapy, long-term follow-up from a randomized trial showed.

Five-year overall survival (OS) was 31.9% in pembrolizumab-treated patients and 16.3% for patients who received chemotherapy. Median OS also was twice as long with pembrolizumab, 26.3 months versus 13.4 months (HR 0.62, 95% CI 0.48-0.81).

The advantage for treatment with the PD-1 inhibitor emerged despite the fact that two-thirds of patients in the chemotherapy group eventually crossed over to the immunotherapy arm, which might have led to underestimation of the magnitude of benefit with pembrolizumab, investigators reported in the .

"This high effective crossover rate may have reduced the observed treatment effect for pembrolizumab versus chemotherapy given that immunotherapy agents (including pembrolizumab) have demonstrated improved OS over chemotherapy in the second line or later setting," said Martin Reck, MD, PhD, of Lung Center Grosshansdorf in Germany, and colleagues. "In a we showed that when OS for patients in the chemotherapy group of was adjusted for crossover ... the HR for OS was 0.49."

"Pembrolizumab provided a durable and clinically relevant long-term OS benefit versus chemotherapy as first-line therapy for metastatic NSCLC [non-small cell lung cancer] with PD-L1 TPS [tumor proportion score] of at least 50% and is a standard-of-care therapy in this setting," they concluded.

The results confirmed and strengthened observations from a previously reported analysis of 3-year survival. The results also are consistent with the KEYNOTE-001 trial, a nonrandomized trial that showed a of 29.6% with single-agent pembrolizumab in treated and untreated metastatic NSCLC.

The KEYNOTE-024 trial compared pembrolizumab and platinum-based chemotherapy as the first treatment for patients with metastatic NSCLC and PD-L1 expression ≥50%. Investigators in the global trial randomized 305 patients to single-agent pembrolizumab or a platinum-based chemotherapy combination. The primary endpoint was progression-free survival (PFS), and OS was a key secondary endpoint.

As , the pembrolizumab arm had a median PFS of 10.3 months versus 6.0 months for the chemotherapy arm (P<0.001). Other secondary endpoints also favored the pembrolizumab arm, including investigator-assessed objective response rate (46.1% vs 31.1%), median duration of response (29.1 vs 6.3 months), median PFS2 (24.1 vs 8.5 months), and median PFS2 at 3 years (39.5% vs 15.0%).

The authors said no new safety signals emerged with longer follow-up in the trial. Treatment-related adverse events (TRAEs), serious TRAEs, and fatal TRAEs (two with pembrolizumab and three with chemotherapy) occurred in a similar proportion of patients in each group.

Immunotherapy's impact on lung cancer survival has been "amazing," said Roy Herbst, MD, PhD, of Yale Cancer Center in New Haven, Connecticut.

"I started doing this work 25 years ago when we were using platinum and taxanes and ifosfamide, and the 1-year survival was 20% or 30% and 2-year survival almost zero, and now we have 5-year overall survival of almost 32%," he told 乌鸦传媒. "This really tells us that we are making amazing progress, and there's a group of patients that I would say are cured from lung cancer."

"These drugs work amazingly well in a reasonable subset of patients and they work okay for the rest of the patients," Herbst added. "We have to figure out how to make it work better for all lung cancer patients and for other types of solid tumors as well."

A key limitation of immunotherapy is the lack of reliable biomarkers to guide treatment to the patients who are most likely to benefit. Future research should include a focus on "personalizing" immunotherapy, as has been done with targeted therapy.

"The problem is we don't know a priori who those patients [who do well] are going to be," said Herbst. "Now is totally the time to personalize immunotherapy. We've taken all of these years personalizing targeted therapy, and now we have seven or eight targets and we're using them quite specifically. We need to do the same thing with immunotherapy so we can help the other 70% or so of patients who don't survive for 5 years."

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