Abstract B31: Single-agent pemetrexed in patients with ALK-positive NSCLC: A retrospective analysis of investigator-reported outcomes
Authors: Salgia R , Ou S I. , Riely G , Kim D W. , Shaw A , Wilner K , Tang Y , Polli A , Scagliotti G V. 
Published: March 2013

Abstract
Recent retrospective data in small patient cohorts have suggested that ALK-positive NSCLC may be particularly sensitive to pemetrexed therapy. Based on investigator-documented tumor response data, we assessed objective response rate (ORR) and time to progression (TTP; based on the Kaplan–Meier method) for patients with ALKpositive NSCLC treated with pemetrexed prior to enrolment in the PROFILE 1005 (NCT00932451; Pfizer) phase 2 multi-center single-arm study of crizotinib.
As of June 1st 2011, 439 ALK-positive patients had been enrolled into PROFILE 1005. All patients had progressed on at least one prior chemotherapy regimen for advanced/metastatic NSCLC. In total, 369 patients (84.1%) had received treatment with pemetrexed prior to enrolment with an ORR of 18.7%. In patients who received secondline single-agent pemetrexed (n=80), ORR was 12.5% and TTP was 5.3 months (95% CI: 3.0–6.6 months). In those who received pemetrexed as third-line or later therapy (n=138), ORR was 16.7%.
Retrospective ORR, TTP and progression-free survival (PFS) data in small ALK-positive patient cohorts have been reported. For example, Camidge et al (J Thoracic Oncol 2011;6:774–780) reported an ORR of 42%, with median PFS of 9 months (95% CI: 3–12 months) in 19 patients who received any-line pemetrexed for ALK-positive NSCLC (including first line combination and maintenance therapy), and Lee et al (J Thoracic Oncol 2011;6:1474–1480) found an ORR of 47%, and median TTP of 9.2 months (95% CI: 4.7–13.7 months) in 15 patients with ALK-positive NSCLC who received pemetrexed as second-line or later therapy.
These figures exceed those reported for larger populations in ALK-untested NSCLC. Scagliotti et al (The Oncologist 2009;14:253–263) reported an ORR of 12.8% and PFS of 3.5 months in 158 patients with adenocarcinoma NSCLC who received second-line single-agent pemetrexed (n=158). Hanna et al (J Clin Oncol 2004;22:1589–1597) reported similar values for second-line single-agent pemetrexed in ALK-untested all-histology NSCLC: ORR 9.1% and median TTP 3.4 months (n=283). Retrospective outcomes data in NSCLC from ALK-positive patients in PROFILE 1005 are therefore more in agreement with data from large unselected populations than from small ALK-positive patient cohorts.
There are limitations of the PROFILE 1005 analysis besides the retrospective nature of the data. These include the availability of investigator-documented rather than independently reviewed tumor response data; strict adherence to RECIST criteria for response data cannot therefore be assured. However, these limitations are countered by the large patient sample size available and narrow confidence intervals reported, supporting the credibility of conclusions drawn from these data. Preliminary efficacy data from PROFILE 1005 for crizotinib in 136 patients with ALK-positive advanced NSCLC found an ORR of 51.1% (95% CI: 42.3–59.9%), with 68.4% of patients still on-treatment at the time of analysis; median duration of response was 41.9 weeks (range 6.1–42.1 weeks; Kim et al, 2011 poster at the European Multidisciplinary Cancer Congress; abstract 9084).
Prospective randomized data are required for a definitive comparison and such a study is currently ongoing. Until these data are available, retrospective data from PROFILE 1005 suggest that the extent of benefit with pemetrexed in terms of ORR and TTP in patients with ALK-positive NSCLC is considerably less than that reported in much smaller retrospective cohorts, and is more consistent with that reported in unselected populations.