Treatment of anaplastic lymphoma kinase (ALK)–positive lung cancer has been one of the great success stories in oncology in the past decade. First discovered in lung cancer in 2007, ALK rearrangements are found in 3% to 5% of patients and define a distinct molecular subgroup of the disease with characteristic clinical and pathologic features.1 Most notably, ALK-rearranged tumors are oncogene-addicted and exhibit marked sensitivity to ALK inhibition.
Indeed, the initial single-arm studies of the ALK inhibitor crizotinib (Xalkori) demonstrated high objective response rates (~60%) and median progression free-survival of 7 to 10 months in ALK-positive patients.2,3 Importantly, these studies validated ALK as a therapeutic target and culminated in the accelerated approval of crizotinib by the U.S. Food and Drug Administration (FDA) in August 2011—just 4 years after the initial discovery of ALK rearrangements in non–small cell lung cancer (NSCLC). This was followed by full regulatory approval of crizotinib in November 2013.
A New Chapter in the Story
As reviewed in this issue of The ASCO Post, Solomon and colleagues have recently added an important new chapter in the story of crizotinib.4 They reported the results of PROFILE 1014, an ongoing, global, randomized phase III trial comparing crizotinib with first-line cytotoxic chemotherapy (platinum-pemetrexed [Alimta]) in previously untreated ALK-positive lung cancer. It should be noted that participants randomized to the chemotherapy arm of this study received a maximum of six cycles of platinum-pemetrexed, but maintenance pemetrexed was not permitted, as this was not considered standard of care at the time of the study design. The primary endpoint of this study was progression free-survival.
Among 343 ALK-positive patients, crizotinib produced significant improvements in median progression free-survival compared with chemotherapy (10.9 vs 7.0 months, P < .001). Crizotinib was also associated with a superior objective response rate (74% vs 45%, hazard ratio [HR] = 0.45, P < .001), greater improvement in global quality of life, and significant reduction in lung cancer symptoms compared with chemotherapy.
Perhaps not surprising, the PROFILE 1014 investigators did not observe differences in overall survival among ALK-positive patients receiving crizotinib compared with chemotherapy. The median overall survival was not reached in either group, and the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy. The lack of a survival benefit in this study likely reflects the fact that 70% of patients initially randomized to chemotherapy crossed over to crizotinib upon disease progression, likely confounding the overall survival analysis.
Impact of First-Line Crizotinib
Although it is always difficult to make cross-trial comparisons, one intriguing aspect of the PROFILE 1014 data is that both the objective response rate and the median progression free-survival for patients treated with crizotinib in the first-line setting appeared greater than those seen in previous studies of crizotinib, including a previous randomized study (PROFILE 1007) that compared second-line crizotinib with single-agent chemotherapy (docetaxel or pemetrexed).5
One potential explanation is that treatment-naive, ALK-rearranged tumors may theoretically be more sensitive to ALK inhibition. Alternatively, there may have been subtle differences in patient populations across trials. For example, although the PROFILE 1007 and 1014 studies generally enrolled similar patient populations, one important distinction is that PROFILE 1014 required treatment of all brain metastases prior to study entry. In contrast, patients with stable, untreated brain metastases were still eligible for participation in PROFILE 1007. As the central nervous system is a frequent site of relapse in ALK-positive patients, this may have affected response rates and progression free-survival in these trials.
Remaining Challenges
The PROFILE 1014 study is important for several reasons. First and foremost, it solidifies the role of crizotinib as a standard of care in the treatment of ALK-positive lung cancer. Furthermore, it again highlights the value of tumor genotyping in the management of lung cancer while also reinforcing the targeted therapy paradigm that was initially established in the treatment of EGFR-mutant lung cancer.
Nevertheless, several important questions and challenges remain. Despite the impressive efficacy of crizotinib in ALK-positive NSCLC, resistance to therapy almost invariably develops—typically within 1 year. Efforts are now underway to elucidate the molecular mechanisms of resistance to crizotinib. To date, resistance mutations in the ALK kinase domain, ALK fusion gene amplification, and upregulation of bypass signaling pathways have all been identified as mechanisms of resistance to crizotinib.6,7 Still, in approximately one-third of crizotinib-resistant tumors, mechanisms of resistance remain unknown.
In addition to understanding the molecular underpinnings of acquired drug resistance, another major obstacle has been to identify approaches to overcome resistance. In ALK-positive NSCLC, current strategies have centered on the use of more potent, structurally distinct ALK inhibitors.
To date, at least eight different next-generation ALK inhibitors are currently in development. One of these agents, ceritinib (LDK378, Zykadia), recently received accelerated approval by the FDA, whereas two other compounds (alectinib and AP26113) have been granted breakthrough therapy designation status. Impressively, all three of these agents have shown high response rates (55%–69%) among ALK-positive patients previously treated with crizotinib.8-10
Such activity in crizotinib-resistant patients has in turn prompted questions about the optimal sequencing of ALK inhibitors. Specifically, could the use of next-generation ALK inhibitors in the first-line setting delay the emergence of resistance, resulting in comparable or even superior durations of response than those observed with sequential ALK inhibition (ie, crizotinib followed by a next-generation ALK inhibitor)?
Moving forward, prospective trials comparing different ALK inhibitors will be important. To that end, the ALEX study (NCT02075840) was recently launched. ALEX is a phase III randomized trial comparing crizotinib with the next-generation ALK inhibitor alectinib in treatment-naive, ALK-positive patients. The primary endpoint for this trial is progression free-survival.
Finally, the report by Solomon and colleagues also raised important questions about drug development and whether it will be necessary to conduct randomized trials comparing highly active targeted agents with chemotherapy—especially as we begin to focus on even rarer, genetically defined patient populations. For example, ROS1 rearrangements are found in 1% to 2% of NSCLC patients. Like ALK, ROS1 is also a target of crizotinib. Earlier this year, Shaw and colleagues reported findings from a single-arm study of crizotinib in ROS1-rearranged lung cancer, demonstrating an objective response rate of 72% and a median progression free-survival of 19.2 months.11 Given this impressive activity, as well as the low frequency of ROS1 rearrangements in lung cancer, it seems unlikely that randomized studies comparing crizotinib with chemotherapy will be feasible. Nonetheless, this may have important implications for the traditional drug development process and raises questions about the necessary benchmarks for regulatory approval of targeted agents in such rare, molecularly defined patient populations.
Moving forward, numerous challenges still remain in the treatment of ALK-positive lung cancer. However, it is also clear that treatment options for these patients have advanced at a remarkable pace. The work by Solomon and colleagues represents another major step forward. ■
Disclosure: Dr. Gainor is a consultant for Boehringer Ingelheim, Kyowa Hakko Kirin Pharma, and Jounce Therapeutics.
References
1. Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561-566, 2007.
2. Kwak EL, Bang YJ, Camidge DR, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693-1703, 2010.
3. Camidge DR, Bang YJ, Kwak EL, et al: Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: Updated results from a phase 1 study. Lancet Oncol 13:1011-1019, 2012.
4. Solomon BJ, Mok T, Kim DW, et al: First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371:2167-2177, 2014.
5. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385-2394, 2013.
6. Katayama R, Shaw AT, Khan TM, et al: Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med 4:120ra17, 2012.
7. Doebele RC, Pilling AB, Aisner DL, et al: Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 18:1472-1482, 2012.
8. Shaw AT, Kim DW, Mehra R, et al: Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 370:1189-1197, 2014.
9. Gadgeel SM, Gandhi L, Riely GJ, et al: Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): Results from the dose-finding portion of a phase 1/2 study. Lancet Oncol 15:1119-1128, 2014.
10. Gettinger S, Bazhenova L, Salgia R, et al: ALK inhibitor AP26113 in patients with advanced malignancies, including ALK+ non-small cell lung cancer (NSCLC): Updated efficacy and safety data. Ann Oncol 25(suppl 4):iv426-iv470, 2014.
11. Shaw AT, Ou SH, Bang YJ, et al: Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371:1963-1971, 2014.
Dr. Gainor is Instructor, Department of Medicine, Harvard Medical School and Assistant in Medicine, Department of Medicine, Massachusetts General Hospital, Boston.
