Crizotinib showed efficacy in lung cancer

The anaplastic kinase inhibitor produced a response rate of 57% in one study, but resistance remains a concern.

Issue: November 25, 2010

Two studies published in October looked at the efficacy and safety of crizotinib, an ATP-competitive inhibitor of the anaplastic lymphoma kinase receptor tyrosine kinase.

Patients diagnosed with lung cancer with EML4–ALK translocation had a strong, lasting response when assigned crizotinib as a second-line treatment, according to findings of a study published in the Oct. 28 issue of The New England Journal of Medicine.

However, a paper by Japanese researchers published in that same issue showed that the tumor cells of patients with lung cancer and the translocation who developed a secondary mutation in the kinase domain of EML4–ALK acquired a resistance to crizotinib.

Writing in an accompanying editorial, Bengt Hallberg, PhD, and Ruth H. Palmer, PhD, both of the department of molecular biology at Umeå University in Umeå, Sweden, said the development of resistance highlights “the need for basic scientists and clinicians to work together to plan a step ahead of the evolving tumor, and that physicians will need additional ALK inhibitors to target EML4–ALK mutants.”

In the first study, Kwak and colleagues analyzed tumor samples from roughly 1,500 patients with non–small cell lung cancer looking for the presence of ALK rearrangements. Eighty-two patients with ALK-positive disease were enrolled on the trial and administered twice daily 250 mg crizotinib.

Researchers said patients in the trial tended to be younger, most had little or no exposure to tobacco and were more likely to be diagnosed with adenocarcinomas compared with those who did not have ALK rearrangements. Seventy-six patients had undergone at least one prior therapy.

After a mean treatment duration of 6.4 months, overall response rate was 57% (95% CI, 46-68). An additional 33% of patients had stable disease, including five who had unconfirmed partial response. The disease control rate was 87% at 8 weeks.

“These results raise the question of whether crizotinib will yield equally strong responses as the first therapeutic intervention or whether a combined approach will be more beneficial,” Hallberg and Palmer wrote. “At a rate of approximately 5% positivity for the ALK rearrangement, the number of potential patients for crizotinib therapy is substantial, approaching 10,000 annually in the United States alone. Clearly, with mutant epidermal growth factor receptor, KRAS and ALK as important clinical determinants in this type of lung cancer, the use of genotyping as standard practice must be considered as a move toward personalized therapy.”

In the other article, Choi and colleagues described the conditions of a 28-year-old man with no smoking history diagnosed with lung adenocarcinoma. The patient was enrolled into the A8081001 study and assigned to twice daily 250 mg crizotinib.

The patient initially responded to therapy, but relapsed at 5 months and eventually withdrew from the study.

Using deep sequencing, the researchers discovered two de novo mutations within the kinase domain of EML4-ALK that conferred resistance to multiple ALK inhibitors. Because they did not find both mutations in any EML4-ALK cDNA, they concluded that each mutation had developed independently.

“Choi et al found that these EML4-ALK mutants are less sensitive to crizotinib than is wild-type EML4-ALK when expressed in Ba/F3 cells, in agreement with the loss of clinical response in this patient,” Hallberg and Palmer wrote. The resistance of the C1156Y variant to crizotinib was not as great in vitro as in vivo, suggesting that this mutation may require interaction with additional factors in the cell to have strong drug sensitivity.”

Taken together, these results suggest the positive outlook for the treatment of ALK-positive lung cancer, Hallberg and Palmer wrote.

“Clearly, in groups of patients with cancers in which ALK is implicated, a standard genotyping approach will be important for a more personalized therapeutic protocol,” they wrote. “Future clinical studies of crizotinib and other ALK inhibitors will tell us whether they will be the latest champions in the cancer wars.”

For more information:

Choi YL. N Engl J Med. 2010;363:1734-1739.

Hallberg B. N Engl J Med. 2010;363:1760-1762.

Kwak EL. N Engl J Med. 2010;363:1693-1703.