Julie R. Brahmer, MD
Long-term survival in patients with metastatic non–small cell lung cancer (NSCLC) who received the immune checkpoint inhibitor nivolumab (Opdivo) has proven to be much higher than expected, with 16% of these patients surviving after 5 years, equivalent to about 4 times what would be expected with chemotherapy.1
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, MD, 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 Ib CA209-003 dose-escalation cohort expansion trial involving 129 patients with heavily pretreated, advanced NSCLC who were randomized to receive nivolumab once every 2 weeks for up to 2 years at 1 of 3 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.2,3
The results Brahmer presented at AACR are based on approximately 5 years of follow-up (minimum follow-up, 58.25 months). Overall survival (OS) at 1 year was 42%; at 2 years, 24%, 3 years, 18%, and at 5 years, OS was 16%. “After 3 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 2 years of nivolumab, “but there were 4 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 2 years of therapy,” Brahmer explained. Additionally and interestingly, she said, “1 patient had early progression, and then had a nonconventional response” to the immunotherapy.
Overall, 12 of the 16 patients received no further therapy after nivolumab, and remained without evidence of progressive disease at the time of their last follow-up, Brahmer reported. Of the 4 patients who received subsequent therapy, 1 stopped therapy after 2 years, and then the disease progressed about 1 year later when the patient was retreated with nivolumab and had a response that lasted about 1 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 <1% PD-L1 (n = 30), and those with ≥1% (n = 38), at 20% and 23%, respectively, Brahmer reported. Of the 13 patients whose tumors expressed ≥50% PD-L1, however, their 5-year OS was 43%. PD-L1 status was not evaluable in 61 patients, but their estimated 5-year OS rate was 10%.
The researchers also analyzed other characteristics of all the treated patients compared with the 5-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 2. “Interestingly, however, 2 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 1 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 nivolumab in February 2011; by April of that year, he demonstrated a partial response. Now, “6 years after nivolumab 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, MD, professor of surgery and director of the Melanoma Program at Johns Hopkins Medicine, who moderated the session. “The 5-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 III nivolumab 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."
- Brahmer JR, Horn L, Jackman D, et al. Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer: clinical characteristics of long-term survivors. Presented at: 2017 AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT077.
- Topalian SL, Hodi, FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-2454. doi: 10.1056/NEJMoa1200690.
- Gettinger SN, Horn L, Gandhi L, et al. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2015;33(18):2004-2012. doi: 10.1200/JCO.2014.58.3708.