Clinical benefit from pemetrexed before and after crizotinib exposure and from crizotinib before and after pemetrexed exposure in patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer

Abstract

Background: Crizotinib produces high response rates and prolonged PFS in ALK+ NSCLC. Retrospective analyses suggest enhanced sensitivity to pemetrexed in crizotinib naive ALK+ NSCLC. Cross-resistance between crizotinib and pemetrexed has not been previously investigated.

Patients and methods: Patients with stage IV ALK+ NSCLC treated with PEM-CRIZ, or CRIZ-PEM were identified. Overall PFS and PFS excluding central nervous system events (eCNS) were compared.

Results: Objective response rates in evaluable patients were 66% (PEM-CRIZ) and 75% (CRIZ-PEM) for pemetrexed and 84% (CRIZ-PEM) and 66% (PEM-CRIZ) for crizotinib. For PEM-CRIZ (n = 29), median PFS and eCNS PFS were both 6 months with pemetrexed, and 10 and 14.5 months, respectively, with crizotinib. For CRIZ-PEM (n = 9), median PFS and eCNS PFS were 4.5 and 3 months, respectively, with pemetrexed, and 8.5 and 7.5 months, respectively, with crizotinib. There was a statistically significant increase in the risk of an overall PFS event with pemetrexed when administered after crizotinib (P = .0277; hazard ratio [HR], 2.5898; 95% confidence interval [CI], 1.1100-6.0424), but differences in the risk of an eCNS PFS event were not significant (P = 0.4913; HR, 1.3521; 95% CI, 0.5727-3.1920). Neither overall nor eCNS PFS for patients while taking crizotinib was associated with a sequence effect relative to pemetrexed.

Conclusion: Crizotinib and pemetrexed are active drugs in ALK+ NSCLC. PFS benefit appeared higher with crizotinib than with pemetrexed. PFS benefit from pemetrexed was less after crizotinib compared with before crizotinib, however, this difference was only statistically significant for overall and not eCNS PFS. Pemetrexed exposure did not seem to affect crizotinib outcomes.

Keywords: ALK; Crizotinib; Lung cancer; NSCLC; Pemetrexed.

Figure 1

Kaplan—Meier Curves for PEM-CRIZ (n = 29) and CRIZ-PEM (n = 9) Cohorts During Pemetrexed Therapy. (A) Overall PFS During the Pemetrexed Portion of Therapy Depicting a Statistically Significant Increase in Overall PFS Events in the CRIZ-PEM Cohort (P = .0277; HR 2.5898; 95% CI, 1.1100–6.0424). (B) Extra-CNS PFS During the Pemetrexed Portion of Therapy Depicting a Trend Toward Increased eCNS PFS Events in the CRIZ-PEM Cohort That was not Statistically Significant (P = .493; HR, 1.3521; 95% CI, 0.5727–3.1920). Median PFS (Rounded to the Half Month) and Range is Provided for Each Cohort Abbreviations: CNS = central nervous system; eCNS = extra-CNS; HR = hazard ratio; PFS = progression-free survival.

Figure 2

Kaplan−Meier Curves for PEM-CRIZ (n = 29) and CRIZ-PEM (n = 9) Cohorts During Crizotinib Therapy. (A) Overall PFS During the Crizotinib Portion of Therapy Depicting a Trend Toward Increased Overall PFS Events in the CRIZ-PEM Cohort That was not Statistically Significant (P = .4223; HR 1.3633; 95% CI, 0.6395−2.9067). (B) Extra-CNS PFS During the Crizotinib Portion of Therapy Depicting a Trend Toward Increased eCNS PFS Events in the CRIZ-PEM Cohort That was not Statistically Significant (P = .3345; HR, 1.4077; 95% CI, 0.7029−2.8189). Median PFS (Rounded to the Half Month) and Range is Provided for Each Cohort Abbreviations: CNS = central nervous system; eCNS = extra-CNS; HR = hazard ratio; PFS = progression-free survival.

Figure 3

Serial eCNS PFS for Individual Patients in the PEM-CRIZ and CRIZ-PEM Cohorts. (A) Overlapping bar Graph Depicting Serial eCNS PFS for Individual Patients Receiving Pemetrexed Then Crizotinib (PEM-CRIZ Cohort). (B) Overlapping bar Graph Depicting Serial eCNS PFS for Individual Patients Receiving Crizotinib Then Pemetrexed (CRIZ-PEM Cohort). ^y Indicates Patients who Have not yet Progressed in any Site With Final Data Censored; ^z Indicates Patients With CNS Progression, who Continue Taking Therapy With Systemic Control; and * Indicates Patients in our Series who Died Before Disease Progression Abbreviations: CNS = central nervous system; eCNS = extra-CNS; PFS = progression-free survival.