RAMASWAMY GOVINDAN, MD
Even though no practice-changing papers were presented at this year's ASCO Annual Meeting, some important abstracts were discussed covering molecular targeted therapies, immunotherapy, and locally advanced non-small cell lung cancer (NSCLC). Due to space constraints, I have limited this discussion to five presentations.
Six years ago, a group of Japanese investigators first reported the presence of a fusion gene involving EML4 and ALK in tumor specimens from patients with NSCLC (so-called ALK-positive NSCLC). Single-agent crizotinib produces a 60 percent response rate in patients with ALK-positive NSCLC with a median progression-free survival in the first-line setting of 18.3 months and 9.2 months in the second-line setting and beyond.
Moreover, crizotinib has been shown to produce better progression-free survival than docetaxel or pemetrexed in the second-line setting.
A number of mechanisms that confer resistance to crizotinib have been identified in patients with ALK-positive NSCLC. These generally fall into two categories: ALK dominant and ALK non-dominant mechanisms of resistance.
Several new ALK inhibitors are now being actively investigated in clinical trials, including CH5424802 (Chugai Pharmaceuticals), ASP3026 (Astellas Pharma), LDK378 (Novartis), and AP26113 (Ariad Pharma). At the ASCO meeting, Dr. Alice Shaw presented results of LDK378 monotherapy in patients with ALK-positive NSCLC (Abstract #8010).
Three groups of patients were enrolled in this study: ALK-positive NSCLC patients who had been treated with crizotinib; ALK-positive NSCLC patients who had not received therapy with crizotinib; and those with cancers other than lung cancer with EML4-ALK rearrangement.
The six-month median progression-free survival rate in the group who received 715 mg of LDK378 was 60 percent. The median progression-free survival for the entire group was 8.6 months. The response rate for patients with ALK-positive NSCLC was 58 percent (N=114). Prior therapy with crizotinib did not affect the response to LDK378. The fact that 57 percent of patients with crizotinib-pretreated ALK-positive disease responded to a second-generation ALK inhibitor was remarkable.
LDK378 was generally well tolerated, with a small number of patients developing nausea and diarrhea. Two ongoing studies are investigating the role of LDK378—one comparing the agent with chemotherapy in patients previously treated with platinum-based chemotherapy and crizotinib (NCT01828112) and another evaluating the agent against chemotherapy in patients who have not received prior crizotinib (NCT01828099).
Also reported were the results of a Phase II study evaluating dabrafenib in patients with BRAF-mutated (V600E) NSCLC (Abstract #8009). The overall response rate among the 20 patients enrolled in this still-ongoing study was 40 percent, with an additional 20 percent of patients achieving stable disease.
The fact that a significant number of patients with BRAF-mutant NSCLC would respond to a specific inhibitor is quite encouraging. It is still too early to assess the impact of dabrafenib on progression-free and overall survival.
Nintedanib is a multi-kinase inhibitor found to be active in a Phase II trial of patients with recurrent NSCLC. A Phase III study (LUME Lung) randomized patients with advanced NSCLC who had developed progressive disease after one line of chemotherapy to either docetaxel and placebo or docetaxel and nintedanib (Abstract #LBA8011).
The study met the primary endpoint of progression-free survival, with a median progression-free survival time of 3.4 months for patients receiving nintedanib and docetaxel, and 2.7 months for those receiving docetaxel and placebo. The overall survival times were 10.1 months for patients receiving the combination and 9.1 months for those receiving docetaxel alone. However, the median overall survival was significantly longer in patients with adenocarcinoma histology with the addition of nintedanib to chemotherapy (12.6 vs. 10.3 months; HR 0.83; 95% CI 0.70-0.99) compared with chemotherapy alone.
This difference in overall survival was not seen in squamous cell histology. The combination regimen was reasonably well tolerated.
It is unclear whether this modest improvement in progression-free and overall survival and adenocarcinoma histology will lead to approval of this agent in the setting. I believe it is critical to develop biomarkers that would clearly identify patients who are likely to respond to this class of agents.
Immunotherapy targeting the checkpoints CTLA4 and PD1 is a topic of great interest in cancer research today. It has been reported previously that PD1-directed therapy produces response in about 15 percent in patients with NSCLC.
At the ASCO meeting, we heard about the response rates with an agent that targets the ligand for PD1 (PDL1), MPDL3280A (Abstract #8008). In this large Phase I study, the response rates in patients with NSCLC were quite encouraging (overall response of 22 percent; with partial responses of 33 percent in patients with squamous cell lung cancer and 19 percent in those with non-squamous cell lung cancer).
Interestingly, the presence of PDL1 in tumor cells is associated with an 80 percent response rate with this agent compared with only 14 percent in patients with no PDL1 expression in the tumor cells.
Even though these results are very intriguing, the number of patients with PDL1-positive NSCLC studied is fairly small (n-5), and the response rate of 14 percent in PDL-negative patients was not trivial.
We need to study a larger cohort of patients with NSCLC before excluding patients based on PDL1 expression from PD1- or PDL1-targeted therapy. A number of ongoing clinical trials are investigating the role of PD1- and PDL1-directed therapy in patients with NSCLC. Combined PD1- and CTLA4-targeted therapy has shown considerable promise in patients with metastatic melanoma, and ongoing studies will hopefully demonstrate similar benefits in patients with advanced NSCLC.
Small institutional studies have previously reported that high-dose (74 Gy) thoracic radiation therapy using a conformal approach resulted in encouraging results compared with historic controls.
The results of an important Phase III study (RTOG 0617) comparing standard-dose (60 Gy) vs. high-dose (74 Gy) conformal radiotherapy concurrent with systemic therapy in patients with locally advanced NSCLC were presented at this meeting (Abstract #7501).
As a planned interim analysis revealed no benefit with high-dose radiation therapy, accrual to the high-dose radiation arm was terminated. Enrollment was, however, continued in the standard radiation therapy arm (to address the role of cetuximab).
This presentation focused on the radiation therapy related issues. The overall survival, the primary endpoint of the study, did not favor the high-dose therapy arm. In fact, the 18-month median survival rates were 67 percent for patients receiving the conventional standard doses of radiation therapy and only 54 percent for those receiving high-dose radiation.
The median overall survival was 28.7 months with standard-dose and 19.5 months with high-dose radiation therapy. Median progression-free survival was 36.6 months with standard-dose radiation and 26.3 months with high-dose therapy. This is an important negative study.
The ongoing work by The Cancer Genome Atlas (TCGA) and other groups will likely shed more light on the genomic landscape of NSCLC. I see a lot of promise in the next-generation ALK inhibitors and immunotherapy directed against PD-1 and PDL-1.
With tumor genotyping becoming standard of care and a number of novel agents under development, the outlook for patients with advanced NSCLC looks promising.