It has now been clearly demonstrated that immune checkpoint inhibitors targeting PD1 and PDL-1 are effective in 20 percent of patients with metastatic non-small cell lung cancer (NSCLC). These drugs are generally well tolerated. Several important studies involving immune checkpoint inhibitors were presented at this year's ASCO Annual Meeting.
The CheckMate 017 study is a randomized Phase III study of nivolumab, a PD1 inhibitor in patients with metastatic squamous cell lung cancer who developed progressive disease following platinum doublet therapy (Abstract 8009). In this study, 272 patients were randomized to receive nivolumab 3 mg/kg body weight intravenously every two weeks until disease progression on docetaxel of the standard dose of 75 mg/m2 intravenously every three weeks. The primary endpoint of the study was overall survival.
The one-year survival rate was 42 percent with nivolumab and 24 percent with docetaxel, and the median overall survival was 9.2 months with nivolumab and 6.0 months with docetaxel. In general, the side effects are extremely well tolerated and the incidence of significant pneumonitis was very low.
One of the notable findings with nivolumab was the median duration of response—an impressive 17.2 months (range of 1.8 to 22.6+) compared with only 5.6 months with docetaxel (range of 1.2+ to 15.2+ months). No biomarkers including PDL1 expression have been found to reliably identify patients who are likely to respond to nivolumab.
CheckMate 057 is a randomized study of nivolumab or docetaxel in metastatic non-squamous NSCLC following disease progression after initial therapy with a platinum doublet (Abstract LBA109). The results were similar to those in CheckMate 017. The median overall survival was 12.2 months for patients on nivolumab and 9.4 months for those on docetaxel, representing a 27 percent decrease in the risk of death for patients who were treated with nivolumab (p=0.0015).
The one-year survival rate for patients who received nivolumab was 51 percent for nivolumab and 39 percent for docetaxel.
Treatment-related adverse events were higher with docetaxel than with nivolumab (any grade was 88% vs. 69% and grades III and IV was 54% vs. 10%, respectively).
These two studies clearly demonstrate the superiority of nivolumab in patients with advanced NSCLC over docetaxel in the second-line setting. Much work remains to be done to fully understand the mechanism of resistance (primary and acquired) to immune checkpoint inhibitors. Several novel immunotherapeutic agents are being tested in the clinic at the present time.
Small Cell Lung Cancer
Two studies presented at the meeting showed encouraging response rates with immune checkpoint inhibitors in patients with small cell lung cancer (SCLC).
The KEYNOTE-028 study is a single-arm Phase II study of a PD1 inhibitor, pembrolizumab, administered at a dose of 10 mg/kg intravenously in patients with SCLC who had progressive disease following platinum-based therapy (Abstract 7502). The overall response rate was 35 percent (95% CI 15-59), and stable disease was reported in an additional five percent of patients.
In the CheckMate 032 study, 40 patients received nivolumab alone and 50 patients received nivolumab with ipilimumab, an anti-CTLA4 antibody (Abstract 7503).
The overall response rate with nivolumab was 18 percent, and the combination produced a response of 17 percent with a median duration of response ranging from 4.1 to 11+ months with nivolumab and 1.1 to 11.1+ months with nivolumab and ipilimumab.
The median overall survival was 4.4 months with nivolumab and 8.2 months with nivolumab and ipilimumab. Ongoing and planned studies will further define the role of immune checkpoint inhibitors in patients with relapsed SCLC.
Several prospective clinical trials have clearly demonstrated that the EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib produce significantly improved response rates and progression-free survival compared with platinum doublets in patients with EGFR-mutant non-small cell lung cancer (NSCLC). Unfortunately, though, the majority of patients with metastatic EGFR-mutant NSCLC develop progressive disease following treatment with EGFR TKIs. The emergence of the EGFR T790M mutation accounts for acquired resistance in nearly 50 percent of patients in this setting.
Two papers published recently in the New England Journal of Medicine reported impressive response rates and promising progression-free survival with the use of third-generation irreversible EGFR TK inhibitors (AZD9291 and rociletinib) that target the EGFR T790M mutation (Jänne et al: NEJM 2015;372:1689-1699andSequist et al: NEJM 2015;372:1700-1709). These two drugs are mutant-specific inhibitors and have very little normal tissue toxicities—i.e., severe rash, diarrhea, etc. The role of these two drugs in the initial therapy of patients with EGFR-mutant NSCLC has not been very well studied.
At this meeting, the preliminary results from a multi-center, multi-cohort study in which patients with EGFR-mutant metastatic NSCLC received AZD9291 either at 80 mg or 160 mg in the front-line setting were presented (Abstract 8000). The overall response rate for the entire group was 73 percent (95% CI: 60, 84) with an impressive disease control rate of 97 percent (95% CI: 89, 100).
The response rate was numerically higher in the 160 mg cohort, with an 83 percent response rate (95% CI: 65, 94) compared with 63 percent in the 80 mg cohort (95% CI: 44, 80).
The progression-free survival rate at 12 months was 72 percent (95% CI of 55-84). It is not possible to estimate the median progression-free survival at this point in view of the immature data.
Based on these preliminary observations, a large Phase III study (FLAURA) has been launched, which will enroll patients with metastatic EGFR-mutant NSCLC in the front-line setting. Patients will be randomized to AZD9291 or a first-generation EGFR TKI (gefitinib 250 mg orally once a day or erlotinib 150 mg orally once a day). The primary endpoint of the study is progression-free survival.
At this point, it is not very clear whether these agents are best utilized in the salvage setting after the development of resistance to first-generation EGFR TKIs or in the frontline setting. Third-generation EGFR TKIs have not yet been approved for use by the U.S. Food and Drug Administration as of July 2015.
It is important to consider biopsy of a growing and accessible lesion to determine the molecular mechanisms of resistance (T790M, Met amplification, etc.) to first-generation EGFR TKIs. Several ongoing studies are evaluating the third-generation EGFR TKIs alone or in combination with inhibitors of VEGF, MEK, C-MET, and immune checkpoints. Every effort should be made to enroll eligible patients in one of these trials.
Since invasive biopsies have certain risks, it is attractive to develop plasma-based assays to detect the emergence of EGFR T790M mutation (Abstract 8001). In the study presented by Dr. Lecia Sequist at this meeting, the response rate to rociletinib was identical whether the T790M was detected through either through plasma-based assay or tissue-based assay. These results are rather encouraging.
It is heartening to see the continued progress in the treatment of patients with ALK-positive NSCLC. The results of a single-arm global Phase II study of alectinib, a novel ALK inhibitor (Abstract 8008) were presented at this meeting. Alectinib produced a response rate of 50 percent in 122 crizotinib-resistant patients, with an encouraging duration of response (11.2 months). Most notably, the disease-control rate (83%) was outstanding, and grade III/IV adverse events occurred in fewer than five percent of patients.
It is likely that we will continue to see progress in the treatment of patients with targeted therapies, with a better understanding of molecular pathogenesis of acquired resistance in certain groups of patients with oncogene-addicted tumors. Continued research efforts hopefully will improve the outcomes in patients with lung cancer who are treated with immune checkpoint inhibitors.