Lauren M. Green
Opdivo (nivolumab) showed better long-term survival rates than expected for patients with metastatic non-small cell lung cancer (NSCLC). In fact, 16 percent of patients survived after five years, about four times what is typically expected for patients on chemotherapy.
What explains the extended survival of these 16 patients, however, remains an important area of further investigation, as the analysis found that nothing really stood out to predict who will become long-term survivors, and the survivors themselves had diverse baseline characteristics.
The study is the first to report long-term survival rates in patients with metastatic NSCLC treated with an immune checkpoint inhibitor. It suggests that, “for a small subset of patients, immunotherapy can work for a very long time,” said study author Julie R. Brahmer, M.D., when reporting the findings during the 2017 AACR Annual Meeting being held April 1 to 5 in Washington, DC.
Brahmer, an associate professor of oncology at the Bloomberg Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, presented updated results from the phase 1b CA209-003 dose-escalation cohort expansion trial involving 129 patients with heavily pretreated, advanced NSCLC who were randomized to receive Opdivo once every two weeks for up to two years at one of three dose levels (1 mg/kg, 3 mg/kg, or 10 mg/kg). Safety and antitumor activity with the anti–PD-1 immunotherapy have been demonstrated and reported in prior studies.
The results Brahmer presented at AACR are based on approximately five years of follow-up (minimum follow-up, 58.25 months). Overall survival (OS) at one year was 42 percent; at 2 years, 24 percent, three years, 18 percent, and at five years, OS was 16 percent. “After three years, the survival curve has plateaued out, which is similar to what has been seen in the past in other diseases treated with immunotherapy,” Brahmer noted.
Twelve of the 16 long-term survivors had partial responses, which includes both early and late responses. Nine patients completed the maximum of two years of Opdivo, “but there were four patients who actually stopped therapy early due to adverse events and have not required any further treatment, even though they didn’t get the full two years of therapy,” Brahmer explained. Additionally and interestingly, she said, “one patient had early progression, and then had a nonconventional response” to the immunotherapy.
Overall, 12 of the 16 patients received no further therapy after Opdivo, and remained without evidence of progressive disease at the time of their last follow-up, Brahmer reported. Of the four patients who received subsequent therapy, one stopped therapy after two years, and then the disease progressed about one year later when the patient was retreated with Opdivo and had a response that lasted about one more year before progression. A second patient stopped therapy and had local progression wherein the right lower nodule was resected, and “this patient has not required any further therapy,” said Brahmer.
Five-year OS was very similar between patients whose tumors expressed less than 1 percent PD-L1 (30 patients), and those with at least 1 percent (38 patients), at 20 percent and 23 percent, respectively, Brahmer reported. Of the 13 patients whose tumors expressed at least 50 percent PD-L1, however, their five-year OS was 43 percent. PD-L1 status was not evaluable in 61 patients, but their estimated five-year OS rate was 10 percent.
The researchers also analyzed other characteristics of all the treated patients compared with the five-year survivors, but, "in general, there is really no difference," Brahmer said. Most patients were former or current smokers, with similar tumor histology: 54 patients in the total cohort had squamous NSCLC and 74 non-squamous; the histology of the 16 long-term survivors was evenly divided between the two. “Interestingly, however, two of the 16 patients had EGFR mutations," noted Brahmer. "Typically, we don't expect these patients to do well with immunotherapy."
The rate of grade 3/4 adverse events was also very similar between the treated patients and the long-term survivors.
Brahmer cited a notable case of one patient at Johns Hopkins, a heavily pretreated 61-year-old male former smoker diagnosed with locally advanced squamous NSCLC in 2008. He progressed after standard therapies and received Opdivo in February 2011; by April of that year, he demonstrated a partial response. Now, “six years after Opdivo treatment initiation, the patient remains alive and well without evidence of progressive disease.” She noted that the patient had a high tumor mutational burden, with 314 total somatic mutations.
“This is the longest follow-up to date on patients with lung cancer receiving this therapy,” noted Suzanne Topalian, M.D., professor of surgery and director of the Melanoma Program at Johns Hopkins Medicine, who moderated the session. “The five-year OS really quadrupled the survival we would otherwise expect if these patients had received chemotherapy."
The findings shed additional light on the important topic of how long patients should remain on immunotherapy. When the phase 3 Opdivo trials were designed, it was unknown how long patients should be treated with the immunotherapy. These findings and other data, said Brahmer, suggest that "we can shorten the time patients require therapy, but we really need to be able to identify those patients who develop 'memory cells' to actually continue to combat their tumor long term.”
She added that ongoing trials are being amended to decrease the time on immunotherapy, but based on the research to date, in her view, "they don't need to be treated indefinitely. But, we want to be able to personalize this therapy and tell when is the best time to stop therapy."