Liz Meszaros, MDLinx | January 10, 2019
Patients with stage IV anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) may have a longer overall survival than previously believed, especially when treated with targeted therapy, according to new research presented in the Journal of Thoracic Oncology.
"What this shows is that with the development of good targeted therapies for ALK-positive lung cancer, even patients with stage IV disease can do well for many, many years," said first author Jose Pacheco, MD, assistant professor, Medicine-Medical Oncology, and investigator, University of Colorado Cancer Center, Aurora, CO.
Dr. Pacheco and colleagues identified 110 patients (median age: 53 years; 83% never-smokers) with ALK+ NSCLC, most of whom (n=105) were treated with crizotinib as their first ALK inhibitor (95%). Most patients presented with stage IV disease (80%), and 20% developed stage IV disease after presenting at an earlier stage. In all, 30% of patients had brain metastasis at the time stage IV disease was diagnosed, and the brain was the only site of metastatic disease in 4.5%. Patients had a median of three organs with metastatic disease at the time of diagnosis of stage IV disease.
After crizotinib therapy, 78% of patients with disease progression were given another ALK-inhibitor, (primarily brigatinib, alectinib, or ceritinib).
After a median follow-up of 47 months, researchers found a median overall survival from the time of diagnosis of stage IV disease of 81 months, or 6.8 years. Overall survival was affected by neither brain metastasis at diagnosis of stage IV disease (P=0.971) nor the year of stage IV presentation (P=0.887).
"A lot of the new ALK inhibitors that were developed after crizotinib get into the brain very well, and they work similarly in the brain when compared to outside the brain. And we're doing more careful surveillance of patients to see when they develop brain mets—instead of waiting for symptoms and then treating, we're monitoring for the development of metastases with imaging of the brain and if we see something new, we sometimes treat it before it causes symptoms," said Dr. Pacheco.
The number of organs with tumors at the time of diagnosis of stage IV disease was the most predictive of worse overall survival (P=0.002), with a hazard ratio of 1.49 for each additional organ with disease. Male sex was also associated with a worse overall survival (P=0.021), as was Hispanic ethnicity.
Finally, Dr. Pacheco and fellow researchers found that each additional month of pemetrexed-based chemotherapy conferred a 7% relative decrease in mortality risk. Patients treated with crizotinib and a next-generation ALK inhibitor after disease progression had a median overall survival of 86 months, compared with 52 months in those not treated with such agents after progression. This suggests that treatment with a next-generation ALK inhibitor after disease progression on crizotinib improves overall survival
"Many studies have reported shorter overall survival for patients with stage IV ALK+ NSCLC treated with crizotinib. These studies had lower survival outcomes in large part because of a lower percentage of patients receiving next-gen ALK inhibitors after progressing on crizotinib. Patients here were getting next-gen ALK inhibitors in phase 1 and 2 clinical trials before many other centers had access to them," said Dr. Pacheco.
The use of pemetrexed-based chemotherapy in these patients also affected survival. Pemetrexed was particularly effective in the treatment of ALK+ disease, according to results from a previous study conducted by D. Ross Camidge, MD, PhD, senior author of this study.
"We try to use mainly pemetrexed-based chemotherapies in ALK+ lung cancer. It is possible shorter survival in other studies may be associated with use of non-pemetrexed based chemotherapies," said Dr. Pacheco.
These results are cause for hope in these patients, in whom historical 5-year overall survival is approximately only 2%. But according to these data, 50% of patients were alive 6.8 years after disease diagnosis.
"At this point, 6.8 years one of longest median survivals ever reported for a NSCLC subpopulation with stage IV disease," said Dr. Pacheco. "It shows the benefit of targeted therapy and how it's changing survival for a lot of patients. And I think it suggests that for some types of NSCLC, it may become much more of a chronic condition rather than a terminal disease."
This study was partially funded by the University of Colorado Lung Cancer SPORE, and the University of Colorado Cancer Center Molecular Pathology Shared Resource. Dr. Pacheco has received consulting fees from AstraZeneca and Novartis, honorarium from Takeda, and research funding from Pfizer.