The prospective phase III PROFILE 1007 study compared the ALK inhibitor crizotinib (Xalkori) to chemotherapy in patients with advanced non–small cell lung cancer (NSCLC) with ALK gene–rearranged tumors refractory to previous chemotherapy. The study showed a clear superiority for crizotinib in terms of progression-free survival (median, 7.7 vs 3.0 months), response rate (65% vs 20%), and symptomatic improvement in this population of patients.

Game-changing Study

Although the results may not be so surprising given the initial data from the phase I/II study of crizotinib (PROFILE 1001), the phase III trial is clearly a game-changing study, since it is the first published randomized trial of crizotinib and it verifies the benefit of an oral ALK inhibitor as single-agent therapy in this particular subgroup of patients. Even though this study—similar to the phase I/II study—was done in chemotherapy-refractory patients, the results will certainly be transferable to clinical practice in first-line therapy.

The fact that PROFILE 1007 showed a significant symptomatic improvement for patients treated with crizotinib is also an important finding, demonstrating that patients not only had prolonged progression-free survival, but actually are doing better on the drug. This study included only patients with good performance status (Eastern Cooperative Oncology Group [ECOG] 0–1), but it is my strong belief that the drug also will benefit ALK-positive patients with poorer performance status. A safety and efficacy single-arm study in patients with poor performance status would most likely verify this.

Another interesting finding in the trial is the outcome on chemotherapy, and particularly the better progression-free survival in the pemetrexed (Alimta)-treated group compared to historical data. This finding verifies the previously reported hypothesis that patients with ALK-rearranged NSCLC do better with pemetrexed—but, of course, still not as well as with an ALK inhibitor. There might be a synergistic effect and/or some biologic association between the two agents, which will be studied in a clinical trial by the Southwest Oncology Group.

ALK Diagnostic Methods

While the PROFILE 1007 study verifies the benefit of crizotinib as single-agent therapy in ALK-positive patients, the results raise some important questions. One question is, How should patients be screened for ALK-gene rearrangement? The U.S. Food and Drug Administration (FDA) has already defined the companion diagnostics for eligibility for crizotinib therapy—namely, Abbott’s ALK–fluorescence in situ hybridization (FISH) assay—using specific criteria, which include 15% or more gene-rearranged cells in the tumor specimen. However, the FDA does not define the method for screening for ALK rearrangement among patients with advanced NSCLC.

Over the past few years, many studies have compared the defined ALK-FISH assay with other ALK diagnostic methods, and a very strong correlation has been found between ALK-FISH and ALK-immunohistochemistry (IHC). In many countries (ie, Japan, European countries), it is recommended that patients be screened with IHC and that positive cases be confirmed with ALK-FISH to determine eligibility for crizotinib therapy or enrollment in clinical studies.

Furthermore, several recent reports have described patients who are ALK-FISH “negative” according to the defined criteria but IHC-positive and who have had dramatic responses to crizotinib. Some of these patients have an “atypical” ALK-FISH pattern that does not fit into the positive category—illustrating the challenges in interpretation of ALK-FISH. In addition, the therapeutic relevance of having NSCLC tumors with less than 15% gene-rearranged cells is still not entirely clear.

Last, but not least, the use of ALK-IHC would reduce screening costs significantly, and IHC is now routinely used for other indications in almost every pathology laboratory around the country. Still, a standardized methodology must be identified for processing and interpreting the IHC assay if it is to be used for screening.

Certainly, the results from the crizotinib studies have moved the therapeutic scenario in lung cancer toward personalized therapy based on molecular testing. The College of American Pathology, International Association for the Study of Lung Cancer, and Association for Molecular Pathology have recently released guidelines for molecular testing in lung cancer, which include guidelines for tissue acquisition, processing, and assay recommendations and interpretations.

Resistance Issues

The PROFILE 1007 study results are very encouraging with regard to the prospect that we might be able to “cure” molecularly defined subgroups of patients in the future—even those with advanced lung cancer, which historically have a dismal prognosis. However, almost all patients will sooner or later develop drug resistance.

Thus, the challenge is to overcome the resistance, and to do that, we need to learn more about resistance mechanisms in order to optimally combine molecularly targeted agents with each other or with conventional chemotherapy. To that end, more clinical studies will need to include rebiopsy for renewed molecular testing at the time of disease progression. In fact, some would argue that rebiopsy at time of progression should be standard practice in patients treated with EGFR tyrosine kinase inhibitors or ALK inhibitors, since we know that some treatable molecular/morphologic changes occur as acquired resistance mechanisms to some targeted therapies.

Potential for ‘Cure’

Based on preliminary clinical results that have been presented, there is reason to believe that some of the new-generation ALK inhibitors are more specific ALK inhibitors than crizotinib and are able to overcome resistance to crizotinib. Other early studies seem to encourage the combination of crizotinib with other molecularly targeted agents.

Thus, the field is rapidly moving toward the potential for “cure” for defined subsets of patients with advanced lung cancer. However, until further mature data are reported, crizotinib is a therapeutic option for patients with ALK-positive advanced NSCLC that should not be missed. Molecular testing of primary NSCLC tumors has become crucial for decisions about therapy for the many patients with advanced NSCLC. ■

Dr. Hirsch is Professor of Medicine and Pathology, University of Colorado Cancer Center, Aurora, Colorado.

Disclosure: Dr. Hirsch reported no potential conflicts of interest.