Crizotinib better than chemo in some ALK-positive NSCLC patients


By Marilynn Larkin

NEW YORK (Reuters Health) - Crizotinib provides better intracranial disease control than chemotherapy in ALK-positive non-small-cell lung cancer (NSCLC) patients with treated, stable brain metastases, multicenter researchers have found.

Crizotinib is an oral small-molecule inhibitor of anaplastic lymphoma kinase (ALK), MET and ROS1 receptor tyrosine kinases. The international phase 3 study PROFILE 1014 recently demonstrated greater progression-free survival, objective response rate, and patient-reported outcomes for crizotinib versus pemetrexed-platinum combination chemotherapy in patients with previously untreated advanced ALK-positive NSCLC, establishing crizotinib as standard first-line therapy in this population, according to the study authors.

However, brain metastases (BM) are frequent in these patients, and those with BM have a poorer prognosis and a median survival time of four to 11 weeks without treatment.

To prospectively compare the intracranial efficacy of crizotinib treatment with that of pemetrexed-platinum chemotherapy in patients with advanced ALK-positive NSCLC, the researchers randomly assigned patients to oral crizotinib 250 mg twice daily (n=172) or intravenous chemotherapy (pemetrexed 500 mg/m2 plus either cisplatin 75 mg/m2 or carboplatin AUC 5 to 6 mg/mL/min -- all given every three weeks for up to six cycles, n=171).

Of 343 patients in the intent-to-treat population, 23% had treated BM at baseline. The researchers observed a nonsignificant intracranial time to tumor progression improvement with crizotinib in the intent-to-treat population (hazard ratio 0.60), in patients with treated BM (HR 0.45), and in patients without BM (HR 0.69).

Among patients with treated BM, the intracranial disease control rate was significantly higher with crizotinib versus chemotherapy at 12 weeks (85% versus 45%, p<0.001) and 24 weeks (56% versus 25%, p=0.006), according to an article online March 28 in the Journal of Clinical Oncology.

Progression-free survival was significantly longer with crizotinib versus chemotherapy in the treated BM subgroup (HR 0.40, p<0.001, median 9.0 vs 4.0 months), in the no BM subgroup (HR 0.51, p<0.001, median 11.1 vs 7.2 months), and in the intent-to-treat population (HR 0.45, p<0.001, median 10.9 vs 7.0 months).

Coauthor Dr. Benjamin J. Solomon, of Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia, told Reuters Health by email that the study "highlights the importance of brain metastases in patients with ALK-rearranged lung cancer and with lung cancer in general, as well as the need to have strategies to deal with this significant clinical problem."

Dr. Jorge Gomez at Icahn School of Medicine at Mount Sinai in New York told Reuters Health by phone that ALK-positive NSCLC patients make up about 4% of NSCLC patients, and so crizotinib "is used in a limited number of patients. But still, we have in the United States about 220,000 lung cancer patients a year, so 4% of that is still a significant number."

"If you have a 2-cm tumor in the lung, it may not cause symptoms for years, but put a 2-cm tumor in the brain and it will swell in that space and squeeze the brain and cause a lot of different potential side effects, such as seizures. So while the number of patients that this study is relevant for is not huge, the impact is very big -- controlling that disease in the brain and giving these patients more time and also better quality of life, since all toxicities were better with the crizotinib than with the chemotherapy in the original study, not just the brain metastases patients," he said.

Dr. Gomez added, "While 12 weeks and 24 weeks are not a huge amount of time for healthy people, patients with ALK rearrangements have a median survival of about 24 months. If you give them a little more time, if you control their disease longer and give them more life, you've made a significant impact on those patients and their families."

"In the real world, we've also treated many patients with untreated brain metastases -- patients who have not had radiation to the brain -- with crizotinib and they've had very good responses. That's enabled us to delay radiation, which can cause a lot of potential side effects, including a decrease in functional capacity and intellectual capacity, for six months or more."

Pfizer supported this research, employed five of the 15 coauthors, and, along with other pharmaceutical companies, had various relationships with nine other coauthors.


J Clin Oncol 2016.

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