Role of Crizotinib in Previously Treated ALK-positive Advanced NSCLC


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In yet another success story for personalized medicine, a targeted therapy extended survival in patients whose cancers expressed the target. Crizotinib (Xalkori), the first-in-class ALK inhibitor, extended progression-free survival and improved response rates compared with single-agent chemotherapy in patients with advanced, previously treated, ALK-positive, non–small cell lung cancer (NSCLC). Compared with chemotherapy, patients in the crizotinib arm had significantly greater improvements in lung cancer symptoms and quality of life as well. These findings of the phase III PROFILE 1007 trial were reported at the Presidential Symposium during the 2012 ESMO Congress in Vienna.1

Rearrangements or translocations in the ALK gene occur in about 5 % of lung cancers, which translates to about 50,000 cases per year, explained lead author Alice Shaw, MD, Massachusetts General Hospital, Boston. Clinical features associated with ALK abnormalities include younger age (average, ~50 years), no smoking history, and adenocarcinoma histology.

“These results establish crizotinib as the standard of care for patients with advanced previously treated ALK-positive NSCLC,” Dr. Shaw told listeners at an ESMO press conference.

Head-to-head Study

PROFILE 1007 is the first head-to-head study comparing crizotinib with standard chemotherapy in NSCLC. The global study, conducted at 105 sites in 21 countries, randomly assigned 347 patients with ALK-positive, stage IIIB or IV NSCLC to crizotinib at 250 mg twice daily, pemetrexed ­(Alimta) at 500 mg/m2, or docetaxel at 75 mg/m2 on a 21-day cycle. All patients had received one prior chemotherapy.

The primary endpoint was progression-free survival assessed by independent radiologic review. Median progression-free survival was 7.7 months with crizotinib vs 3 months with chemotherapy, representing a 51% reduction in risk of progression for the ALK inhibitor (P < .0001). Comparing crizotinib with pemetrexed and docetaxel separately, median progression-free survival was 7.7 months with crizotinib vs 4.2 months with pemetrexed (P = .0004 compared with crizotinib) vs 2.6 months with docetaxel (P < .0001). Crizotinib tripled the overall response rate compared with chemotherapy: 65.3% vs 19.3%, respectively (P < .0001).

An interim analysis showed no difference in overall survival between the two arms, but Dr. Shaw said the data are immature and that the majority of patients in the chemotherapy arms crossed over to crizotinib. “This makes determining overall survival very challenging,” she stated.

Adverse Events

Toxicities of crizotinib were mild and manageable. Most grade 3 or 4 toxicities with crizotinib were observed in fewer than 5% of patients, with the exception of elevated transaminases (16%), pulmonary embolism (5%), and neutropenia (13%).

Time to deterioration in lung cancer symptoms was significantly delayed with crizotinib (5.6 months with crizotinib vs 1.4 months with chemotherapy, P < .0001). Also, patient-reported quality of life was significantly improved with crizotinib (P < .0001).

Median progression-free survival was less than 8 months, and it is expected that resistance to crizotinib will develop, Dr. Shaw explained. Investigational drugs that also target ALK are in early-phase trials; these include LDK378, AP26113, and heat shock protein 90 inhibitors.

Crizotinib was granted accelerated approval from the FDA in August 2011, for locally advanced or metastatic ALK-positive NSCLC.

Remaining Questions

At the ESMO press conference, Fortunato Ciardello , MD, Seconda Università di Napoli in Naples, Italy, said, “This shows that a selective specific inhibitor of a molecular target makes a big difference in treatment outcome. We need to define the underlying genetics and then select therapy accordingly.”

Formal discussant of the PROFILE 1007 presentation, Jean Charles Soria, MD, Institut Gustave Roussy, Paris, congratulated the investigators on this “amazing” phase III randomized trial showing extended progression-free survival and improved quality of life. He also cited some remaining questions: “How should we implement this in daily practice? Now that we have a biomarker, who should pay for it, what is the optimal technique, optimal sample, and tissue availability?” Dr. Soria continued.

He added that EGFR and ALK testing should not be done separately. Rather, patients should be tested for different molecular abnormalities. In France, 24,000 patients have been tested for EGFR and only 4,000 for ALK, he noted.

Practice Variations

In the United States, National Comprehensive Cancer Network (NCCN) guidelines for NSCLC call for ALK and EGFR testing, and this is done at major comprehensive cancer centers. It is less clear whether community oncologists are routinely testing for EGFR and ALK, Dr. Shaw said at the press conference.

Dr. Soria was critical about the slowness of the European approval process, noting that crizotinib has been approved in the United States for more than 1 year but is not yet approved in Europe.

“There is a different attitude between FDA and EMA [European Medicines Agency]. The EMA needs to establish risk vs benefit. It took 5 months for the FDA to approve crizotinib and it took 14 months for EMA to call for more data,” he stated. On average, there is an 8-month lag between approval in the United States and Europe, he added.■

Disclosure: Dr. Soria has received honoraria from Pfizer. Drs. Shaw and Ciardello reported no potential conflicts of interest.

Reference

1. Shaw AT, Kim DW, Nakagawa K, et al: Phase III study of crizotinib versus pemetrexed or docetaxel chemotherapy in patients with advanced ALK-positive non-small cell lung cancer (PROFILE 1007). 2012 ESMO Congress. Abstract LBA1. Presented September 30, 2012.


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