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Pemetrexed benefited lung cancer patients with ALK mutations
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Patients with lung adenocarcinoma who have anaplastic lymphoma kinase gene mutations derived greater benefit from pemetrexed-based therapy than those without the mutations, according to results of a retrospective analysis performed in Korea.
Benefits observed in this patient population included a higher response rate and longer PFS.
Jae Cheol Lee
Crizotinib (Xalkori, Pfizer) remains the drug of choice for front-line treatment of patients with ALK-positive lung cancer, but in Korea, it is not covered by insurance. Because many patients cannot afford the cost, other front-line chemotherapeutic agents should be considered, researchers wrote.
Pemetrexed (Alimta, Eli Lilly), a targeted thymidylate synthase inhibitor, received FDA approval for treatment of patients with nonsquamous non–small cell lung cancer when combined with cisplatin or carboplatin as a front-line treatment. Pemetrexed also can be used as a single-agent treatment in the second-line or maintenance settings.
Jae Cheol Lee, MD, PhD, of the division of oncology at the University of Uslan Medical College at Asan Medical Center in South Korea, and colleagues conducted a retrospective analysis of outcomes in patients with lung adenocarcinoma who underwent chemotherapy with pemetrexed. They assessed whether outcomes varied between patients with anaplastic lymphoma kinase (ALK)-mutated disease and those with ALK wild-type disease.
“ALK inhibitors such as crizotinib and ceritinib (Zykadia, Novartis) are highly active in ALK-positive lung cancer,” Lee told HemOnc Today. “However, the development of resistance to these drugs is inevitable, requiring the elucidation of the role of other chemotherapeutic drugs. A recent study showed that PFS on pemetrexed monotherapy or nonplatinum/pemetrexed combinations was similar in ALK-positive and ALK wild-type patients, which was contrasted with the results of previous two small retrospective studies. In order to address this issue, we compared the benefits of pemetrexed-based treatment between lung adenocarcinoma patients with ALK and other gene alterations, such as EGFR and KRAS.”
The analysis include 442 patients with lung adenocarcinoma treated at Asan Medical Center between January 2010 and March 2014. The patients were divided into four groups based on gene alterations: 52 were ALK-positive, 188 had epidermal growth factor receptor (EGFR) mutations, 34 had KRAS mutations and 168 had wild-type disease.
Patients received 500 mg/m2 pemetrexed intravenously every 21 days. The majority of patients (n=311) received pemetrexed alone, whereas 125 patients received it in combination with cisplatin or carboplatin, and six patients received pemetrexed in combination with nonplatinum agents. Treatment continued until disease progression, unacceptable toxicity or death.
Fourteen of the ALK-positive patients had received prior crizotinib.
The median follow-up was 15.7 months (range, 1.7-99.4 months). In that time, 73.8% of the patients died, and 8.8% were still undergoing treatment with a pemetrexed regimen at the time of data cutoff.
Researchers reported a significantly higher response rate among ALK-positive patients (26.9%) than those with EGFR-mutant disease (12.8%), KRAS-mutant disease (8.8%) or wild-type disease (18.5%; P=.046).
A subgroup analysis of patients who received single-agent pemetrexed in the second-line setting or beyond showed a similar benefit. In that cohort, response rates were 29% among patients with ALK-positive disease, 8.4% for those with EGFR-positive disease, 8.7% for those with KRAS-mutant disease and 11.8% for those with wild-type disease (P=.013).
Researchers observed no significant difference in response rate when pemetrexed combination therapy was used as front-line treatment. In that analysis, response rates were 22.2% among ALK-positive patients, 20% in EGFR-positive patients, 11.1% in KRAS-mutant patients and 33.3 in patients with wild-type disease (P=0.448).
Median PFS among all patients was 3 months (95% CI, 2.3-3.7. Researchers reported longer median PFS among patients with ALK-positive disease (7.8 months) than those with EGFR-mutant disease (2.5 months), KRAS-mutant disease (2.3 months) and wild-type disease (2.9 months; P<.001).
The PFS benefit was more evident among patients who received pemetrexed monotherapy. In that subgroup, median PFS was 8.7 months among those with ALK-positive tumors, 2 months for those with EGFR-mutant tumors, 1.6 months for those with KRAS-mutant tumors and 1.9 months for those with wild-type disease (P<.001).
“Lung adenocarcinoma with ALK rearrangement shows a higher [response rate] to pemetrexed,” Lee said. “PFS with pemetrexed is better in ALK-positive patients, survival benefit is more evident when pemetrexed is used as single agent [and] nonsmoking status confers a prolonged PFS to pemetrexed.
“We suggest that pemetrexed should be preferentially considered for the treatment of ALK–positive lung adenocarcinoma when use of ALK inhibitors is not feasible. Further investigations to define the underlying mechanism related with the sensitivity to pemetrexed in ALK-positive lung cancer should be followed.” – by Anthony SanFilippo
Jae Cheol Lee, MD, PhD, can be reached at Asan Medical Center of Ulsan, College of Medicine, 86 Asanbyeongwon-gil, Songpa-Gu, Seoul, 138-736, Korea; email: jclee@amc.seoul.kr.
Disclosure: The researchers report no relevant financial disclosures.
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