Megan Brooks

April 19, 2015

PHILADELPHIA — The programmed death (PD-1) inhibitor pembrolizumab (Keytruda, Merck) has durable antitumor activity in advanced non-small cell lung cancer (NSCLC), especially in the setting of high PD-L1 tumor expression, where the response rate tops 45%, according to results from the KEYNOTE-001 study.

"I think with these data we can now confidently say that in previously treated patients who have PD-L1 expression in at least half of their cells...pembrolizumab is associated with superior clinical outcomes [to] what would be anticipated with cytotoxic chemotherapy. In addition, the outcomes in patients with lesser degrees of staining may also be better," said Edward Garon, MD, from the David Geffen School of Medicine at the University of California, Los Angeles.

He discussed the findings here today at the American Association for Cancer Research (AACR) 2015 Annual Meeting, with simultaneous publication in the New England Journal of Medicine.

Pembrolizumab is currently approved for use in melanoma and is being studied in other tumor types including NSCLC.

In the KEYNOTE-001 study, 495 patients with advanced NSCLC received pembrolizumab (2 mg/kg or 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks) until disease progression, death, withdrawal from the study, or development of intolerable toxicity.

There was no clear difference in efficacy or safety by dose, and going forward, the 2 mg/kg every 3 weeks schedule will be studied, Dr Garon reported.

He noted that the toxicity profile in NSCLC was "very manageable." Fatigue, pruritus, and decreased appetite were the most common treatment-related adverse events. Adverse events of grade 3 or higher were reported in 47 (9.5%) patients, a proportion lower than that anticipated with chemotherapy. Nine patients (1.8%) developed pneumonitis of grade 3 or greater, including 1 (0.2%) who died. Other immune-related adverse events occurring in at least 2% of patients were infusion-related reactions (3.0%) and hypothyroidism (6.9%).

The overall response rate (ORR) for the entire cohort was 19.4% (95% confidence interval [CI], 16.0% - 23.2%), with no clear difference by prior treatment status. The ORR was 18.0% (95% CI, 14.4% - 22.2%) in the 394 previously treated and 24.8% (95% CI, 16.7% - 34.3%) in the 101 previously untreated patients.

The median duration of response exceeded 1 year (12.5 months) in all responders regardless of the degree of PD-L1 expression, "which is one of the exciting outcomes with this class of drug," Dr Garon said in a news release. The median response duration was 10.4 months in previously treated patients and 23.3 months in previously untreated patients.

Median progression-free survival was 3.7 months (95% CI, 2.9 - 4.1 months) for all patients, 3.0 months (95% CI, 2.2 - 4.0 months) for previously treated patients, and 6.0 months (95% CI, 4.1 - 8.6 months) for previously untreated patients.

Median overall survival was 12.0 months (95% CI, 9.3 - 14.7 months) for all patients, 9.3 months (95% CI, 8.4 - 12.4 months) for previously treated patients, and 16.2 months (95% CI, 16.2 months to not reached) for previously untreated patients.

A Biomarker of Response

Using a prototype immunohistochemical assay for PD-L1 expression developed for the study, the researchers showed that patients with PD-L1 expression in at least 50% of tumor cells are more likely to respond to pembrolizumab.

Table. Objective Response Rate by PD-L1 Tumor Level

Patients ≥50% (95% CI) 1% to 49% <1%
Total 45.2% (33.5% - 57.3%) 16.5% (9.9% - 25.1%) 10.7% (2.3% - 28.2%)
Previously treated 43.9% (30.7% - 57.6%) 15.6% (8.3% - 25.6%) 9.1% (1.1% - 29.2%)
Previously untreated 50.0% (24.7% - 75.3%) 19.2% (6.6% - 39.4%) 16.7% (0.4% - 64.1%)

With 50% or higher PD-L1 expression, median progression-free survival with pembrolizumab therapy was 6.3 months (95% CI, 2.9 - 12.5 months) compared with 3.3 months (95% CI, 2.1 - 4.1 months) and 2.3 months (95% CI, 2.1 - 4.0 months) with 1% to 49% and less than 1% PD-L1 expression, respectively.

Median overall survival among patients with at least 50% PD-L1 tumor expression has not been reached in the total population (95% CI, 13.7 months to not reached), regardless of prior treatment.

Briefing moderator Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland, said the results are "especially impressive," given that three quarters of the patients had previous systemic therapy and had progressive disease after that.

Alex A. Adjei, MD, PhD, a thoracic oncologist and researcher at Roswell Park Cancer Institute in Buffalo, New York, who was not involved in the study, told Medscape Medical News, "This is certainly an important study, and further evidence that immunotherapy is going to be of benefit in lung cancer."

He noted that nivolumab (Opdivo, Bristol-Myers Squibb) was the first PD-1 inhibitor to be approved for NSCLC. "The interesting/different thing about this study is that they used PD-L1 expression as a biomarker in an attempt to better identify the patients who are likely to respond," said Dr Adjei.

D. Ross Camidge, MD, PhD, director, thoracic oncology clinical and clinical research programs, University of Colorado Comprehensive Cancer Center in Denver, and AACR discussant for the study, said there is no doubt that PD-1 axis blockade has been a "major breakthrough" in the therapy of solid tumors, and this study sheds more light on the search for who derives the most benefit, at least in NSCLC.

"We've known with this whole class of agents for some time that they don't work in everybody," he noted in an interview with Medscape Medical News. PD-L1 tumor expression is "not a perfect biomarker. It doesn't guarantee that you're going to benefit from the drug, it just increases the chance. And it doesn't say if you don't have the biomarker you won't benefit, but it's the best level of enrichment that we've seen, and because it's in such a large dataset, it's got the potential to be a companion diagnostic."

The study was funded by Merck. Dr Garon's institution received funds to conduct the trial, but he has no other conflicts of interest. Dr Adjei has no disclosures. Dr Camidge has disclosed advisory roles with Array, Eli Lilly, Immunogen, Novartis, Genentech/Roche, Biodesix, AstraZeneca, Clarient, Excelixis, and IndiPharm; and received honoraria and research funding from Ariad.

American Association for Cancer Research (AACR) 2015 Annual Meeting: Abstract 9109. Presented April 19, 2015.

N Engl J Med. Published online April 19, 2015. Full text

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