In pooled analyses from NP28673 and NP28761, alectinib showed activity against systemic and CNS disease in patients previously treated with crizotinib.3,4 Alectinib demonstrates effective CNS penetration and is not a substrate for P-glycoprotein, which promotes efflux at the blood–brain barrier.8 Responses in the alectinib Phase II studies were durable, lasting for longer than 1 year.3 In the exploratory analyses presented here, we investigated how quickly patients can achieve benefit from alectinib. Systemic and CNS responses were rapid (median 6–8 weeks), and most patients achieved a response by the time they underwent their first scan. This trend was consistent when patients were analyzed by measurable and/or non-measurable baseline CNS disease or measurable baseline disease only, indicating that the onset of clinical activity is not impacted by the lesion being measurable or non-measurable. It is important to note that TTR also included patients with CNS disease for whom quick response in the CNS contributed to the overall rapid systemic response.

The previously published pooled analysis from NP28673 and NP28761 showed that alectinib is also effective in patients with CNS metastases at baseline who had not received prior radiotherapy.4 Our exploratory analyses identified a rapid TTCR in patients with baseline CNS metastases who had not received prior radiotherapy, indicating that a lack of prior radiotherapy does not impact how rapidly these patients respond to alectinib. TTCR is critical in determining the appropriate therapy, especially for symptomatic CNS disease where radiation is considered a standard of care and is associated with rapid symptomatic improvement. While our analysis is limited by the timing of radiographic assessments, future studies incorporating both clinical symptom assessment and imaging at earlier time points may be helpful to determine whether alectinib TTR can be confirmed within an earlier timeframe, which would aid the management of symptomatic CNS metastases. The documented penetration and activity of alectinib in the CNS suggest that it may be possible to substitute alectinib for radiation in some circumstances.

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These exploratory analyses have some limitations, which should be considered when interpreting the data. Patient numbers for some of the subgroup analyses are small, and the data should therefore be interpreted with caution. In addition, pseudoprogression is a well-defined phenomenon that can occur within 3 months of radiotherapy completion due to radiation necrosis. However, it is not possible to account for pseudoprogression in NSCLC metastases in the CNS, as the current RECIST criteria lack an outline for determining pseudoprogression in non-primary CNS solid tumors. In the NP28673 and NP28761 studies, 20% and 53% of patients, respectively, were enrolled less than 6 months after completing radiotherapy,4,6,7 so it is possible that some patients identified as having disease progression may actually have had pseudoprogression.

Three Phase III studies have demonstrated superiority of alectinib compared with crizotinib in patients with either treatment-naïve or ALK inhibitor-naïve ALK+ NSCLC (treatment-naïve in ALEX [NCT02075840] and ALESIA [NCT02838420]; ALK inhibitor-naïve in J-ALEX [JapicCTI-132316]).9–11 All three studies included patients with untreated baseline CNS metastases, and all demonstrated prolonged PFS with alectinib versus crizotinib (median PFS ALEX, 34.8 months vs 10.9 months;9 ALESIA, NE months vs 11.1 months;10 J-ALEX, 34.1 months vs 10.2 months).11

Alectinib also consistently demonstrated superior efficacy in the CNS versus crizotinib across all three first-line studies. In ALEX, the hazard ratio (HR) for time to CNS progression, without prior non-CNS progression, was significantly longer with alectinib versus crizotinib; HR 0.18 (95% CI: 0.09–0.36) in patients with baseline CNS metastases, and 0.14 (95% CI: 0.06–0.33) in patients without baseline CNS metastases.12 In ALESIA, alectinib significantly decreased the risk of CNS progression without prior non-CNS progression compared with crizotinib (cause-specific HR 0.14; 95% CI 0.06–0.30).10

In J-ALEX, alectinib demonstrated superiority to crizotinib in preventing the onset of CNS metastases (HR 0.19, 95% CI 0.07–0.53) and in patients with brain metastases at baseline, prevented CNS progression compared with crizotinib (HR 0.51, 95% CI: 0.16–1.64).13

Median PFS in patients with CNS metastases at baseline was superior for alectinib versus crizotinib in all three trials (ALEX, 27.7 months [95% CI: 9.2–NE] for alectinib versus 7.4 months [95% CI: 6.6–9.6] for crizotinib [HR 0.35; 95% CI: 0.22–0.56];9 ALESIA, NE months for alectinib versus 9.2 months for crizotinib [HR 0.11; 95% CI: 0.05–0.28];10 J-ALEX, 25.9 months [95% CI: 17.5–NE] for alectinib versus 10.3 months [95% CI: 6.5–14.2] for crizotinib [HR 0.47; 95% CI: 0.19–1.18]).13 In patients without baseline CNS metastases, median PFS for alectinib was also superior for alectinib in all three studies (ALEX, 34.8 months [95% CI: 22.4–NE] for alectinib versus 14.7 months [95% CI: 10.8–20.3] for crizotinib [HR 0.47; 95% CI: 0.32–0.71];9 ALESIA, 20.3 months for alectinib versus 12.7 months for crizotinib [HR 0.34; 95% CI: 0.18–0.65];10 J-ALEX, NE months [95% CI: 20.3–NE] for alectinib versus 10.2 months [95% CI: 8.3–12.1] for crizotinib [HR 0.36; 95% CI: 0.23–0.56]).13

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These data suggest that many patients could be spared the toxicity of radiation by using a targeted therapy, such as alectinib, that is effective both systemically and in the CNS.

In summary, the data reported here demonstrate that alectinib can achieve a rapid response in both untreated and previously treated patients with ALK+ NSCLC, both systemically and in the CNS. Further investigation into the early clinical benefit (<6 weeks) is warranted to evaluate alectinib for the initial treatment of CNS metastases and the potential for sparing radiation therapy.

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