Crizotinib Shows Promise Against Non-Small-Cell Lung Cancer

More than half of select patients with advanced non–small-cell lung cancers responded to treatment with crizotinib, according to findings of a phase I multicenter clinical trial reported in the Oct. 28 issue of the New England Journal of Medicine.

Crizotinib inhibits the anaplastic lymphoma kinase (ALK) gene’s receptor, tyrosine kinase, which has been linked to several types of cancer.

In a group of 82 patients, many of whom had undergone numerous anticancer therapies for advanced ALK-positive tumors, the overall partial and complete response rate was 57%, and disease stabilized in an additional 33%. These results are "impressive" compared with the approximately 10% response rate seen in similar cancers treated with second-line multiagent chemotherapy, said Dr. Eunice L. Kwak of Massachusetts General Hospital Cancer Center, Boston, and her associates.

The probability of 6-month progression-free survival was estimated to be 72% with crizotinib therapy, compared with a rate of 27% for similar tumors treated with second-line chemotherapy.

The dose of oral crizotinib was escalated from 50 mg once daily to 300 mg twice daily. Dose-limiting fatigue was noted at this level, so the maximal dose was cut back to 250 mg twice daily.

A total of 46 patients met RECIST criteria for a partial response and 1 for a complete response to the drug, for an overall response rate of 57%. An additional 27 patients met criteria for stable disease.

Treatment response was quite rapid, with a disease-control rate of 87% at 8 weeks.

The rapid response to crizotinib "suggests that ALK-positive tumors constitute a second genetically defined subgroup of oncogene-driven lung cancer that is highly susceptible to targeted therapy," the investigators noted.

Nausea and diarrhea were the most common adverse effects. Thirty-four patients (41%) reported mild visual disturbances, but no abnormalities were detected on ophthalmologic examination.

Four patients showed elevated alanine aminotransferase (ALT) levels and 5 showed elevated aspartate amino transferase (AST) levels, all of which reverted to normal when crizotinib was discontinued. Four of these patients were able to resume the treatment at a lower dose without recurrence of this toxicity.

A total of 63 patients (77%) continued to receive crizotinib after the conclusion of the study and continue to be followed.

These findings demonstrate the importance and feasibility of genotyping to individualize treatment. They also show that non–small-cell lung tumors with ALK rearrangements – which occurred in approximately 5% of the patients screened for participation in this trial – are highly sensitive to ALK kinase inhibition, Dr. Kwak and her colleagues said (N. Engl. J. Med. 2010;363:1693-703).

Two separate case reports published in the same issue of the journal further delineated outcomes with crizotinib therapy.

In the first, a 28-year-old man with large tumor nodules in one lung, multiple enlarged lymph nodes in the mediastinum, atelectasis, and massive effusion in the right pleural cavity showed a marked initial response to the crizotinib within 1 week. However, after 5 months of treatment his tumor "abruptly started to grow again, resulting in a rapid expansion of the pleural effusion and the development of tumors in both lungs," said Dr. Young Lim Choi of Jichi Medical University, Tochigi, Japan, and associates.

Suspecting that the cancer may have acquired genetic changes that conferred resistance to crizotinib, the researchers identified in sputum and effusion specimens two de novo mutations within the kinase domain of the ALK gene. "We do not know whether the resistant clones were present initially or developed secondarily, during treatment," they noted (N. Engl. J. Med. 2010;363:1734-9).

It is likely that an as-yet unidentified mechanism is present in oncogenic tyrosine kinases, which facilitates the development of further mutations that confer resistance to many ALK inhibitors. Further research should shed light on this process and lead to the development of next-generation ALK inhibitors that address the mutations and the resistance they confer, Dr. Choi and colleagues added.

In the second case study, two patients with another type of cancer – inflammatory myofibroblastic tumors (IMTs) – were given crizotinib empirically. It was hoped that the drug would show activity in these patients because approximately half of IMTs carry rearrangements of the ALK gene, said Dr. James E. Butrynski of the Dana-Farber Cancer Institute, Boston, and his associates.

The first patient was a 44-year-old man whose extensive peritoneal and mesenteric cancer had recurred after surgical excision; peritoneal perfusion with combined cisplatin, doxorubicin, and mitomycin C; further treatment with doxorubicin and ifosfamide; and maintenance therapy with imatinib. The patient responded to daily crizotinib beginning in December 2008 and has maintained complete radiographic remission until press time.