Kate Johnson

April 03, 2017

WASHINGTON – The longest follow-up to date on patients treated with nivolumab (Opdivo, Bristol-Myers Squibb) for advanced non-small cell lung cancer (NSCLC) shows a 16% 5-year overall survival (OS) rate, according to new results presented here at the American Association for Cancer Research annual meeting.

Before immunotherapy, 5-year survival in this setting was approximately 4%, said investigator Julie Brahmer, MD, from Johns Hopkins University School of Medicine, Baltimore, at a meeting press conference.

The new data come from the phase 1b CA209-003 study, which is the first trial of any programmed death-1 (PD-1) immune checkpoint inhibitor in lung cancer.

"It should be noted that the 5-year overall survival really quadrupled the survival that we would otherwise expect if these same patients had received chemotherapy," said Suzanne Topalian, MD, also from Johns Hopkins and a coinvestigator.

"Before immunotherapy, the majority of patients with advanced disease died within a year after diagnosis," "added Dr Brahmer.

Initial results from the trial ( J Clin Oncol. 2015 Jun 20;33[18]:2004-2012) were "a landmark in the history of immunotherapy for cancer," said Dr. Topalian.  The findings in lung cancer effectively brought this approach "out of the realm of a specialized treatment and into the broader arena of oncology," leading to FDA approval of nivolumab for second-line treatment of patients with advanced NSCLC.

However, the new long-term results, while good news, still offer no clues about either predictors of long-term survival, or when patients might be able to stop therapy.

According to the trial design, patients received a maximum of 2 years of therapy, but currently the standard of care is to treat them indefinitely, explained Dr Brahmer. "This study showed that once treatment stopped, 75% of patients maintained responses without other cancer therapy…. So I think based on this study and others we can say that they don't need to be treated indefinitely…but we want to be able to better personalize this therapy to tell when is the best time to stop."

The study included 129 patients who had previously received between 1 to 5 lines of systemic therapy. Subjects were randomly assigned to 3 possible doses of nivolumab (1, 3, or 10 mg/kg once every 2 weeks) and then followed for a minimum of 58 months.

About 50% of the patients had enough tumor to stain for PD-L1, showing that patients with levels of less than 1% had 5-year OS rates of 20% compared with a 43% OS among those with PD-L1 levels of 50% or more.

"We're looking at this prospectively but due to the small numbers of patients there was really no statistical difference between the groups. We saw improved survival across all PD-L1 staining," said Dr Brahmer.

Asked by Medscape Medical News to comment, Irene La-Beck, PharmD, from Texas Tech University Health Sciences Center School of Pharmacy in Abilene, said, "The results from this study are very promising and would be the first clinical evidence we have to suggest that PD-1-targeted immunotherapy can achieve durable responses in NSCLC patients."

However, Dr La-Beck, who recently published a paper on nivolumab in NSCLC ( Ther Clin Risk Manag. 2017 Feb 21;13:223-236), said these findings need to be verified in phase 3 trials.

"The 5-year OS rates from CheckMate-017 and CheckMate-057, expected within the next couple of years, will more decisively answer this question," she said. 

Dr La-Beck pointed out that the study "was not randomized, blinded, or controlled, so it is more susceptible to bias than a phase 3 trial. It compared outcomes to historical data, and we have no way of knowing how the standard of care treatment of the historical cohort would compare to the current standard of care treatment for NSCLC patients. And the investigators also used three different doses, so I don't know how generalizable these results are to patients getting the current FDA-approved dose."

As for what the findings say about PD-L1 status, it remains unclear, she said.

"One of the challenges in this area right now is how to identify patients who are likely to respond to PD-1 targeted therapy, because it is a very costly regimen and the evidence we have so far shows that only a minority of patients will benefit," Dr La-Beck continued.

"It is worth noting that they did see durable responses in patients with <1% PD-L1 expression and this is in contrast with pembrolizumab, which is only indicated in NSCLC patients with >50% PD-L1 expression. But the sample size in this study is too small to make any conclusion about the relationship between patient characteristics and treatment responses.

"This study would suggest two things: PD-L1 status alone may not be a sufficiently robust biomarker for patient selection; and some criteria for patient selection is clearly needed," she concluded.

The study was funded by Bristol-Myers Squibb (BMS). Dr Brahmer received research funding from BMS and is an advisor to the company. Dr Topalian reports relevant relationships with BMS as well as AbbVie, Five Prime Therapeutics, ImaginAb, Amgen, Aduro, Compugen, Jounce Therapeutics, MedImmune, Merck, Nextimmune, Pfizer, Potenza Therapeutics, Sanofi, and Tizona. Dr La-Beck reported research funded by the NIH's National Cancer Institute and the Development Corporation of Abilene. She disclosed no other relevant financial relationships. 

American Association for Cancer Research 2017 Annual Meeting: Abstract CT077. Presented April 3. 2017.

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