Long-term survival in stage IV ALK-positive non-small cell lung cancer (NSCLC) improved dramatically following the introduction of ALK inhibitors, a retrospective, single-center analysis showed.
The 110 patients treated with ALK inhibitors had a median overall survival (OS) of almost 7 years. In contrast, historical 5-year survival for unselected patients with newly diagnosed stage IV NSCLC was 2%. Brain metastasis at diagnosis did not adversely affect survival, nor did the year of stage IV diagnosis, reported Jose Pacheco, MD, of the University of Colorado Cancer Center in Aurora, and colleagues in the Journal of Thoracic Oncology.
“This really illustrates well the benefits you can have with precision medicine targeted toward specific genetic mutations,” Pacheco said. “As we learn more about ALK-positive lung cancer, these newer treatments that we are developing will improve on the [survival] numbers that we report.”
“Traditionally, people have thought a diagnosis of stage IV lung cancer meant that they don’t have a lot of time to live. I think that with appropriate treatment with molecular therapy, it will become increasingly common for patients with specific mutations to live quite a long time,” he added. “Perhaps, even, moving more toward a chronic disease and away from something that’s sort of short term.”
The findings added new evidence of the impact of precision medicine in advanced NSCLC, particularly ALK-positive disease. A small retrospective study showed a 5-year OS of 36% for patients with stage IV ALK-positive NSCLC who received crizotinib (Xalkori), the first approved ALK inhibitor, as initial therapy. A randomized clinical trial showed a 4-year OS of 57% with crizotinib as initial therapy for stage IV ALK-positive NSCLC.
Two other retrospective analyses suggested median OS ranging from 49 to 89 months for patients treated with crizotinib followed by a next-generation ALK inhibitor at progression.
Pacheco and colleagues reported survival for patients treated from 2009 through November 2017 for stage IV ALK-positive NSCLC with any of four approved ALK inhibitors: crizotinib, ceritinib (Zykadia), alectinib (Alecensa), and brigatinib (Alunbrig). Investigators excluded patients who did not have ALK-positive tumors, or who had more than one type of malignancy.
Medical records showed that all but five of the 110 patients with stage IV ALK-positive NSCLC received crizotinib as their initial ALK inhibitor. Patients in the comparator group received systemic therapies that included chemotherapy, immunotherapy, and other agents that were not ALK inhibitors.
In the ALK-positive group, 88 patients had stage IV disease at diagnosis and 22 progressed to stage IV after diagnosis at an earlier stage. More than 80% of the patients had never smoked, 33 had brain metastases at diagnosis of stage IV disease, and the group had a median of three metastatic sites.
The ALK-positive patients had a median follow-up of 47 months. They had a median OS of 81 months (6.8 years) from diagnosis of stage IV disease (range 3-125 months). The 4- and 5-year survival rates was 73% and 60%, respectively. In contrast, data from the Colorado Cancer Center’s tumor registry showed that 973 patients with molecularly unselected stage IV NSCLC had a median survival of 0.75 years.
Median survival did not differ significantly between patients who received crizotinib as their initial treatment (n=40, 86 months) and those who received something other than an ALK inhibitor as initial systemic therapy (n=65, 79 months). The remaining five patients received a next-generation ALK inhibitor as initial therapy and did not have sufficient data for a survival comparison.
A multivariate analysis comprising 102 patients showed that brain metastasis at diagnosis of stage IV disease did not significantly influence OS (HR 1.01, P=0.971), nor did year of stage IV diagnosis (2004-2017, P=0.887). Increased number of involved organs (HR 1.49 per each additional organ, P=0.002), and male sex (HR 2.38, P=0.021) were associated with worse OS. Additionally, patients who received pemetrexed (Alimta)-based therapy, before or after crizotinib, had a 7% reduction in the relative risk of death for each month of therapy (P=0.03).
All but three patients who received crizotinib as the initial ALK inhibitor had disease progression during treatment. Median time on crizotinib was 14 months, and the median time to first progression was 11 months.
Seeking to build on the foundation established with first-generation ALK inhibitors, investigators hope to see additional survival improvement with early use of next-generation ALK inhibitors. Randomized clinical trials demonstrated substantially better outcomes among patients with advanced ALK-positive NSCLC treated initially with alectinib or brigatinib as compared with crizotinib, Pacheco noted.
“The numbers are quite a bit better than we would have expected if we gave crizotinib followed by [one of the newer drugs],” he told MedPage Today. “As we move these newer ALK inhibitors into first line, as opposed to crizotinib, I think the median survivals we see, the long-term survivals, will increase over time.”
The study was supported by the University of Colorado Lung Cancer SPORE and the University of Colorado Cancer Center Molecular Pathology Shared Resource. Some co-authors disclosed support from the University of Colorado Lung Cancer SPORE.
Pacheco disclosed relevant relationships with AstraZeneca, Novartis, Takeda, and Pfizer. Some co-authors disclosed multiple relevant relationships with industry including AstraZeneca, Roche/Genentech, Pfizer, and Takeda.