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Pembrolizumab reduces need for second-line therapy in advanced NSCLC
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CHICAGO — A significant improvement in PFS after first-line therapy allowed more patients with non–small cell lung cancer treated with pembrolizumab than chemotherapy to avoid progressing to second-line therapy, according to updated results of the KEYNOTE-024 trial presented at the ASCO Annual Meeting.
Further, fewer patients who received pembrolizumab (Keytruda, Merck) than chemotherapy experienced progression after the next line of therapy, also called PFS2.
“We know that pembrolizumab has robust, durable antitumor activity and is generally well tolerated in both treatment-naive and previously treated NSCLC that expresses PD-L1,” Julie R. Brahmer, MD, co-director of the upper aerodigestive department of Bloomberg-Kimmel Institute for Cancer Immunotherapy and associate professor of oncology at Johns Hopkins Medicine, said during her presentation. “It also has activity in combination with pemetrexed and carboplatin for treatment-naive nonsquamous cell histology patients.”
Previously reported results from KEYNOTE-024 showed pembrolizumab is superior to chemotherapy as first-line therapy for advanced NSCLC with a PD-L1 tumor progression score of 50% or greater and no sensitizing EGFR mutations and ALK translocations. Researchers reported HRs of 0.5 for PFS (P < .001) and 0.6 for OS (P = .005).
These data led to FDA approval of pembrolizumab in the first-line setting, Brahmer said.
Brahmer and colleagues conducted follow-up of KEYNOTE-024 to update OS data and report on PFS2, an exploratory endpoint of the trial.
European Medicines Agency in 2012 first defined PFS2 as time from randomization to objective tumor progression in the next-line treatment or death from any cause, whichever came first.
“We looked at this to assess the potential impact of crossover on OS assessment, as well as to assess whether therapy positively or negatively affected efficacy in the next line of therapy,” Brahmer said.
The analysis included 154 patients (median age, 64.5 years; 59.7% men) randomly assigned 200 mg pembrolizumab every 3 weeks and 151 patients (median age, 66 years; 62.9% men) assigned platinum-doublet chemotherapy with optional pemetrexed maintenance for nonsquamous histology. Patients in the chemotherapy arm could cross over to pembrolizumab upon disease progression.
Brahmer noted at baseline more patients in the pembrolizumab arm had brain metastases (11.7% vs. 6.6%), whereas more patients in the chemotherapy arm had liver metastases (23.8% vs. 13%) and had received prior radiation therapy (28.5% vs. 22.7%).
Median follow-up was 19.1 months at the data cutoff of Jan. 5, 2017.
Forty-six patients remained on first-line pembrolizumab compared with only one patient in the chemotherapy arm.
Median duration of treatment was 3.5 months (range, 1 day to 22.9 months) with chemotherapy and 7.9 months (range, 1 day to 23.5+ months) with pembrolizumab.
Treatment discontinuation occurred in 107 patients in the pembrolizumab arm and 120 in the chemotherapy arm. More patients on the chemotherapy arm discontinued due to progressive disease (76 vs. 63) and death (10 vs. 7), whereas more patients on the pembrolizumab arm discontinued due to adverse events (28 vs. 18).
In total, 48 patients (31.2%) in the pembrolizumab arm received second-line therapy compared with 97 patients (64.2%) in the chemotherapy arm. This included 79 patients who crossed over from chemotherapy to pembrolizumab (median treatment duration, 4.2 months) and 12 patients who received anti–PD-1 therapy outside of crossover (median treatment duration, 3 months), for an effective crossover rate of 60%.
Most patients who received second-line therapy after pembrolizumab received a platinum doublet (87.5%), with a median treatment duration of 3.6 months.
PFS2 data favored patients who received pembrolizumab first over chemotherapy.
Median PFS2 was 18.3 months with pembrolizumab and 8.4 months with chemotherapy (HR = 0.54; 95% CI, 0.4-0.72). More patients treated with pembrolizumab first achieved 18-month PFS2 (51% vs. 24.6%).
Updated OS data maintained consistent superiority of first-line pembrolizumab (median, not reached vs. 14.5 months; HR = 0.63; 95% CI, 0.46-0.88). Researchers reported 18-month OS rates of 61.2% in the pembrolizumab arm and 43% in the chemotherapy arm.
“Pembrolizumab continues to show an OS benefit over chemotherapy as first-line treatment for advanced NSCLC with a PD-L1 tumor proportion score of at least 50%,” Brahmer said. “Despite an effective crossover rate of 60%, there remains a high degree of separation of the OS curves. PFS2 was substantially improved for patients in the pembrolizumab arm, and patients whose tumors have PD-L1 tumor proportion score of at least 50% have better survival if beginning treatment with pembrolizumab than a platinum-doublet chemotherapy. These data support pembrolizumab as a first-line treatment of NSCLC.” – by Chuck Gormley and Alexandra Todak
Reference:
Brahmer JR, et al. Abstract 9000. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Disclosure: Brahmer reports consultant/advisory roles with Bristol-Myers Squibb, Celgene, Janssen Oncology, Lilly, Merck and Syndax; and research funding or travel accommodations from AstraZeneca, Bristol-Myers Squibb, Five Prime Therapeutics, Incyte, Janssen Oncology and Merck. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Cardinale Smith, MD
Checkpoint inhibitors are a great new line of therapy for our patients with cancer and these data suggest, as in other cancers, pembrolizumab (Keytruda, Merck) can play an even stronger role than chemotherapy. Immunotherapy is becoming the way we are treating cancer.
We know already that first-line treatment of immunotherapy is better than chemotherapy for someone who has PD-L1 expression of greater than 50%. These data further show that, because the PFS in this study is so much longer, patients are not getting as many lines of therapy because their first-line therapy is working much longer.
The impact is that we now have these immunotherapies that, in terms of side effect profiles, are much better tolerated. We have better treatments to give to patients with incurable diseases. Although we are prolonging their lives, providing them with good quality of life at the same time is essential, and these new treatments are helping us do that.
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