Positive Results in ALK-Positive NSCLC With First ALK Inhibitor

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Crizotinib extended PFS and improved response rates compared with single-agent chemotherapy with pemetrexed or docetaxel in patients with advanced, previously treated, ALK-positive, NSCLC.

Alice T. Shaw, MD, PhD

Crizotinib, the first-in-class ALK inhibitor, extended progression-free survival (PFS) and improved response rates compared with single-agent chemotherapy with pemetrexed or docetaxel in patients with advanced, previously treated, ALK-positive, non-small cell lung cancer (NSCLC), according to the results of the phase III PROFILE 1007 trial presented September 30 at the ESMO 2012 Congress in Vienna. Crizotinib achieved a greater improvement in lung cancer symptoms and quality of life (QOL) compared with chemotherapy.

“This is the first head-to-head study comparing crizotinib with standard chemotherapy in NSCLC. These results establish crizotinib as the standard of care [in the US] for patients with advanced previously treated ALK-positive (ALK+) NSCLC,” stated lead author Alice T. Shaw, MD, PhD, Dana-Farber/Harvard Cancer Center, Boston. Crizotinib (Xalkori, Pfizer) is FDA-approved for the treatment of ALK+ NSCLC.

ALK rearrangement, occurring in 3% to 5% of lung cancers, is one of several genetic changes that can drive lung cancer. Because of the high prevalence of lung cancer cases, ALK+ cases account for more than 50,000 new cases of NSCLC each year, Shaw said.

Several studies have identified distinct clinical features associated with ALK abnormality, she continued. These factors include younger age (10 to 15 years younger); no smoking history; and adenocarcinoma.

PROFILE 1007 was a global study conducted at more than 100 sites in 20 countries. The study randomized 347 patients with ALK+, stage IIIb or IV NSCLC to crizotinib 250 mg/bid; pemetrexed 500 mg/m2; or docetaxel 75 mg/m2 on a 21-day cycle. Median number of cycles of treatment was 11 for crizotinib and 4 for chemotherapy.

The study met its primary endpoint of progression-free survival (PFS): median PFS was 7.7 months with crizotinib versus 3.0 months with chemotherapy, representing a 51% reduction in risk of progression for the ALK inhibitor (P < .0001). Looking at the two chemotherapy drugs separately, median PFS was 7.7 months with crizotinib versus 4.2 months with pemetrexed (P = .0004 compared with crizotinib) versus 2.6 months with docetaxel (P < .0001).

According to independent radiologic review, crizotinib tripled the overall response rate compared with chemotherapy: 65.3% versus 19.3%, respectively (P < .0001).


An interim analysis showed no difference in overall survival between the two arms, but Shaw said the data are immature and also confounded by crossover to crizotinib from the chemotherapy arms.

Toxicities of crizotinib were mild and manageable, she continued. The rate of grade 3/4 toxicities was under 5% with the exception of elevated transaminases reported in 16% of patients and pulmonary embolism in 5%. The rate of myelosuppression was higher with chemotherapy compared with crizotinib.

QOL was superior for crizotinib-treated patients, based on patient reported outcomes regarding time to deterioration in lung cancer symptoms: median of 5.6 months with crizotinib versus 1.4 months with chemotherapy (P < .0001).

Fortunato Ciardiello , MD, PhD, Seconda UniversitaÌ€ di Napoli in Naples, Italy, emphasized the importance of this study. “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.”

The availability of genetic testing and reimbursement depends on the country. “In the US, genetic testing is available at major cancer centers, which follow the NCCN guidelines to offer EGFR and ALK testing upfront to lung cancer patients,” Shaw said. “I don’t know if community oncologists do this testing,” she added.

With a median PFS of 7 months, patients will develop resistance to this targeted therapy. Two next-generation ALK inhibitors are in phase II studies—LBK 178 and AB6 273—and heat shock protein inhibitors are also under study. These new agents may prove useful in patients who become resistant to crizotinib, she said.

Shaw AT, et al. Phase 3 randomized study of crizotinib versus pemetrexed or docetaxel chemotherapy in advanced, ALK-positive NSCLC (PROFILE 1007). Vienna, Austria: European Society for Medical Oncology; September 30, 2012. Abstract LBA1.


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