Treatment Focus: What New Research Means for Crizotinib

Patients with non-small cell lung cancer (NSCLC) withALKrearrangements account for a small minority (4%) of patients with NSCLC. NSCLC withALKrearrangement occurs more often in patients with lung cancer who are nonsmokers and in patients with a history of smoking of 10 pack-years or fewer.¹

In its normal function,ALKacts to regulate cell signaling, including signaling to downstream signaling pathways, such as the RAS—mitogen-activated protein kinase pathway, thePI3K/AKTpathway, and theJAK/STATpathway. Activation of theALKgene through translocation and formation of fusion proteins may lead to formation of cancerous cells that demonstrate uncontrolled proliferation and survival.¹

Early retrospective studies indicated a survival benefit with use of crizotinib in patients withALKrearrangements.^2,3In one retrospective study, Berge et al analyzed records of patients withALKrearrangements treated with pemetrexed followed by crizotinib, and reported improved outcomes compared with patients receiving crizotinib followed by pemetrexed. Median progression-free survival(PFS)was 4.5 months with pemetrexed following crizotinib versus 8.5 months with crizotinib following pemetrexed. The risk of progression was significantly greater with pemetrexed than with crizotinib as secondary therapy (hazard ratio [HR] 2.59;P= .0277).²

In another retrospective study, Shaw et al analyzed data indicating an advantage in overall survival (OS) in patients with NSCLC and theALKrearrangement treated with crizotinib. Investigators analyzed data from 67 patients with theALKrearrangement and 253 patients withoutALKrearrangements. Patients were well matched based on age, sex, smoking history, and ethnicity. Compared with patients with theALKrearrangement who received standard chemotherapy instead of crizotinib, patients who received crizotinib had a significantly lower risk of progression (HR, 0.36;P= .004) and a longer OS after 1 year (70% vs 44%) and 2 years (55% vs 12%).³Early retrospective studies indicated a survival benefit with use of crizotinib in patients with ALK rearrangements.^2,3In one retrospective study, Berge et al analyzed records of patients withALKrearrangements treated with pemetrexed followed by crizotinib, and reported improved outcomes compared with patients receiving crizotinib followed by pemetrexed. Median progression-free survival (PFS) was 4.5 months with pemetrexed following crizotinib versus 8.5 months with crizotinib following pemetrexed. The risk of progression was significantly greater with pemetrexed than with crizotinib as secondary therapy (hazard ratio [HR] 2.59;P= .0277).²

In another retrospective study, Shaw et al analyzed data indicating an advantage in overall survival (OS) in patients with NSCLC and theALKrearrangement treated with crizotinib. Investigators analyzed data from 67 patients with theALKrearrangement and 253 patients withoutALKrearrangements. Patients were well matched based on age, sex, smoking history, and ethnicity. Compared with patients with theALKrearrangement who received standard chemotherapy instead of crizotinib, patients who received crizotinib had a significantly lower risk of progression (HR, 0.36;P= .004) and a longer OS after 1 year (70% vs 44%) and 2 years (55% vs 12%).³

Studies confirm crizotinib’s superior efficacy compared with standard chemotherapy in patients with lung cancer who haveALKrearrangements and mutations.⁴

In June 2013, investigators published results of a prospective study of crizotinib in theNew England Journal of Medicine.⁵In a press release, lead investigator Alice T. Shaw, MD, PhD, who is affiliated with the Massachusetts General Hospital Cancer Center in Boston, stated, “This is the first randomized study to compare crizotinib with standard chemotherapy in advancedALK-positive lung cancer.” The trial involved 347 patients who had experienced a progression of NSCLC after receiving earlier treatments. Patients received either crizotinib orally twice daily or standard treatment with every-3-week intravenous infusions of docetaxel or pemetrexed.^4,5

Among patients receiving crizotinib, nearly two- thirds (65%) of patients responded to therapy versus one-fifth (20%) of patients receiving standard chemotherapy (P <.001). Overall PFS averaged 7.7 months in patients receiving crizotinib versus 3 months in patients receiving standard chemotherapy. According to Shaw, &ldquo;This study shows that patients with advancedALK-positive lung cancer respond better to crizotinib and for longer periods of time.&rdquo;^4,5

Investigators speculated that an OS was not found between groups because of patient crossover from the standard chemotherapy group to the crizotinib group.⁴

These results confirm the efficacy of crizotinib and support its use as a standard-of-care treatment for cases of advanced NSCLC with evidence ofALKrearrangements. This recommendation is supported by the latest guidelines from the National Clinical Cancer Network (NCCN).^1,6

In addition to its efficacy against tumors with theALKrearrangement, crizotinib has separate effects on 2 other mutations: theMETamplification and theROS1rearrangement. According to the NCCN guidelines, crizotinib is the only known agent to act against these 2 cancer mutations.6-8 Early cell line studies indicate that NSCLC with bothROS1mutations andALKrearrangements may be more sensitive to crizotinib than NSCLC withALKrearrangements alone.⁷In addition, in a case report, a patient with NSCLC with a MET amplification and without anALKrearrangementresponded to treatment with crizotinib.⁸Future trials will evaluate the role of crizotinib patients with these mutations.

Crizotinib improves PFS in patients with advanced NSCLC andALKrearrangements. However, the developing understanding of the spectrum of activity of crizotinib may lead to its use in select patients with ROS1 mutations and MET amplifications.^7,8Understanding the full spectrum of activity of crizotinib could lead to an expanded use of crizotinib that may benefit more patients with NSCLC.

References

1. Shaw AT, Engelman JA.ALKin lung cancer: past, present, and future.J Clin Oncol.2013;31(8):1105-1111./li>
2. Berge EM, Lu X, Maxson D, et al. Clinical benefit from pemetrexed before and after crizotinib exposure and from crizotinib before and after pemetrexed exposure in patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer.Clin Lung Cancer.2013;14(6):636-643.
3. Shaw AT, Yeap BY, Solomon BJ, et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouringALKgene rearrangement: a retro- spective analysis.Lancet Oncol.2011;12(11):1004-1012.
4. Marquedant K. Massachusetts General Hospital. MGH-led studies shed new light on targeted lung cancer therapy [press release]. http://www.eurekalert.org/pub_releases/2013-06/ mgh-mss053013.php. Published June 1, 2013. Accessed August 2014.
5. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advancedALK-positive lung cancer.N Engl J Med.2013;368(25):2385-2394.
6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. Version 4.2014. www.nccn.org. Accessed August 2014.
7. Bergethon K, Shaw AT, Ou SH, et al.ROS1rearrangements define a unique molecular class of lung cancers.J Clin Oncol.2012;30(8):863-870.
8. Ou SH, Kwak EL, Siwak-Tapp C, et al. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non- small cell lung cancer patient with de novoMETamplification.J Thorac Oncol.2011;6(5):942-946.