Long-term survival in stage IV NSCLC


In this edition of “How I will treat my next patient,” I highlight two studies addressing long-term survival for patients with stage IV non–small cell lung cancer (NSCLC). One summarizes survival of patients who received nivolumab therapy in the second- or later-line setting. The other is a retrospective database query regarding whether local consolidation (LC) improves survival after systemic treatment of patients with oligometastatic NSCLC.

Dr. Alan P. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis.

Dr. Alan P. Lyss

Nivolumab therapy

Scott J. Antonia, MD, PhD, and colleagues sought to determine the frequency of long-term survival among advanced NSCLC patients who received nivolumab in the second-line or later settings (Lancet Oncol. 2019 Aug 14. doi: 10.1016/S1470-2045[19]30407-3). They aggregated the results of four trials. Checkmate 017 and 057 were phase 3 comparisons of nivolumab with docetaxel for nonsquamous and squamous NSCLC, respectively – with crossover from docetaxel to nivolumab permitted. Checkmate 003 was a dose-escalation trial and Checkmate 063 was a phase 2 study of nivolumab in advanced, refractory squamous NSCLC. A minimum follow-up of 4 years was required.

In total, 664 patients participated in the four trials, more than 85% of whom received the fairly standard dose of 3 mg/kg every 2 weeks. In a very data-dense analysis, among all patients who received nivolumab, the 4-year overall survival was 14% (95% confidence interval, 11%-17%). Four-year overall survival was higher (19%; 95% CI, 15%-24%) in patients with at least 1% programmed death-ligand 1 (PD-L1) expression. There was no difference by histology (squamous vs. nonsquamous). Patients with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, PD-L1 greater than 10%, and absence of liver metastases were more likely to achieve 4-year overall survival.

Although progression-free survival was low (8%, overall; 19% for patients achieving complete remission or partial remission), depth of response correlated with the 4-year overall survival rate. Those patients in complete or partial remission at 6 months had an overall survival at 4 years of 56%. Stable disease at 6 months showed an overall survival at 4 years of 19%, which was superior to the results for patients with partial disease as best response (4%).

There were two treatment-related deaths with nivolumab, with no unexpected safety signals. Despite allowing continuous treatment in three of the four studies, most potentially immune-related toxic events occurred in the first 2-3 years of therapy. In the two randomized studies (017 and 057), 4-year overall survival was higher with nivolumab (14%) than with docetaxel (5%), with no overlap in the 95% confidence intervals.

What this means in practice

British prime minister, Benjamin Disraeli (and, later, Mark Twain) said, “There are three kinds of lies: lies, damned lies, and statistics.” There are no lies in Dr. Antonia’s paper, but there are plenty of statistics – which oncologists love. The reported data enable us to put some boundaries on the figures we quote when patients ask us, “How well could I do with this treatment?” Dr. Antonia’s paper significantly assists with these very practical discussions. For patients who want more detail, the boundaries can be further refined. Dr. Antonia and colleagues have given us clinical (depth of response, performance status, sites of metastasis) and molecular (proportion of cells with PD-L1) refinements to personalize our consultations with patients.

Unfortunately, the data do not allow us to predict who should not receive an immune checkpoint inhibitor and, instead, receive late-line chemotherapy or early hospice referral. The data summarize well-executed clinical trials, but it is well known that (as reported at the Quality Care Symposium 2019) NSCLC patients participating in clinical trials have significantly improved survival rates – perhaps as much as two times – compared with those not enrolled in trials. These realities, however, should not obscure the fact that immune checkpoint inhibitors are a major advance for metastatic NSCLC patients, including those who have progressed after prior treatment. They offer hope for cancer-free or cancer-controlled survival that would have properly been placed in the category of “a miracle” just a few years ago.


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