Crizotinib Beats Chemo in ALK-Positive Advanced NSCLC

Laurie Barclay, MD

June 03, 2013

June 3, 2013 — The targeted agent crizotinib (Xalkori) is superior to standard chemotherapy in patients with previously treated advanced nonsmall-cell lung cancer (NSCLC) and anaplastic lymphoma kinase (ALK) gene rearrangement, according to a phase 3 open-label trial published online June 1 in the New England Journal of Medicine.

These results were first presented last year at the European Society of Medical Oncology meeting, as reported at the time by Medscape Medical News. The data were described as practice-changing by Fortunato Ciardiello, MD, PhD, professor of medical oncology at the Second University of Naples in Italy. "There was a huge difference in favor of crizotinib.... The risk of progression is reduced by 50%, and you rarely see this in any metastatic solid tumor," he said at the time. The results of this trial show that crizotinib "is the best option for treatment in these patients," he added.

"This study demonstrates the value of testing lung cancer tissue for an ALK rearrangement, and it underscores the potential of cancer genomics to target cancer treatments to each patient," senior author Pasi A. Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts, said in a news release. "ALK now becomes the second abnormal gene that we are able to successfully target in lung cancer with drugs other than chemotherapy."

The first such gene is the epidermal growth factor receptor (EGFR) gene, and EGFR inhibitors are now commonly used before the initiation of chemotherapy. In single-group studies, patients with ALK rearrangements have had marked clinical responses to crizotinib.

Chromosomal rearrangement of ALK occurs in only about 5% of NSCLC cases, but given that there are nearly 200,000 cases of NSCLC in the United States each year, more than 5000 new patients could benefit from treatment with crizotinib, Dr. Jänne and colleagues note.

Phase 3 Trial Design and Results

The study involved 347 patients with locally advanced or metastatic ALK-positive lung cancer treated with 1 previous platinum-based regimen. Patients were randomized to oral crizotinib 250 mg twice daily, or to chemotherapy with intravenous pemetrexed (500 mg/m²) or docetaxel (75 mg/m²) every 3 weeks. Progression-free survival was the main study end point.

As part of a separate analysis, patients in the chemotherapy group with disease progression were allowed to cross over to crizotinib.

Median progression-free survival was longer in the crizotinib group than in the chemotherapy group (7.7 vs 3.0 months). The hazard ratio for progression or death with crizotinib was 0.49 (95% confidence interval [CI], 0.37 - 0.64; P < .001). The response rate was higher in the crizotinib group than in the chemotherapy group (65% vs 20%; P < .001).

Overall survival was similar in the 2 group (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 - 1.54; P = .54).

Visual disorder, gastrointestinal adverse effects, and elevated liver aminotransferase levels were common adverse events in the crizotinib group, but were generally mild (grade 1 or 2). However, 3 patients in the crizotinib group (2%) had treatment-related interstitial lung disease of grade 3 or higher, and 2 of them died. In the chemotherapy group, common adverse events were fatigue, hair loss, and shortness of breath.

"Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy," write Dr. Jänne and colleagues. "Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced [NSCLC] with ALK rearrangement."

One of the limitations of this study is the difficulty comparing overall survival because of crossover from the chemotherapy to the crizotinib group.

"Compared with standard second-line chemotherapy, treatment with crizotinib resulted in significantly longer progression-free survival, significantly higher response rates, a significant reduction in symptoms, and a significant improvement in global quality of life," Dr. Jänne and colleagues conclude. "In this study, crizotinib was more effective than either pemetrexed or docetaxel."

Resistance to Crizotinib

An accompanying case report describes a patient who developed resistance to crizotinib.

"Resistance to crizotinib developed in a patient with metastatic lung adenocarcinoma harboring a CD74–ROS1 rearrangement who had initially shown a dramatic response to treatment," write Mark M. Awad, MD, PhD, from the Massachusetts General Hospital Cancer Center, and colleagues. "We performed a biopsy of a resistant tumor and identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding."

The 48-year-old woman presented with progressive dyspnea and a malignant pleural effusion. The effusion continued to worsen on chemotherapy, but her dyspnea, fatigue, and loss of appetite improved dramatically within 1 week of starting treatment with crizotinib 250 mg twice daily. Repeat CT scan of the chest after 2 months of treatment with crizotinib confirmed substantial clinical response with reduction in effusion.

One month later, while she was still taking crizotinib, her respiratory symptoms worsened, and chest imaging showed disease progression. At autopsy, all metastatic sites examined had the same resistance mutation, suggesting that the mutation occurred early in the clonal evolution of resistance to crizotinib.

"Despite the genetic heterogeneity that has been identified at various metastatic sites in an individual patient, our findings support the notion that some oncogenic drivers are present in founder clones and therefore may be present at all sites of metastasis," Dr. Awad and colleagues conclude. "It is also noteworthy that the same mechanism of acquired resistance — the G2032R mutation — was identified at all the sites of disease that were examined, and no other ROS1 kinase mutations were identified by deep sequencing. Thus, it appears that this mutation occurred early in the development of resistance and suggests that a potent inhibitor of this mutant kinase may have been clinically effective after the failure of crizotinib."

This study was funded by Pfizer. Three of the study coauthors are employees of the company.

N Engl J Med. Published online June 1, 2013. Abstract, Case report

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