Activity With ALK Inhibitor Sequencing Sparks Hope for Patients With NSCLC

Targeted Therapies in OncologySeptember 2019
Volume 8
Issue 12

Based on findings from retrospective analyses and clinical trial data, patients with <em>ALK</em>-rearranged non&ndash;small cell lung cancer may be able to receive sequential ALK inhibitors following progression with similar second and third-generation agents.

Based on findings from retrospective analyses and clinical trial data, patients withALK-rearranged non—small cell lung cancer (NSCLC) may be able to receive sequential ALK inhibitors following progression with similar second and third-generation agents.

&ldquo;Data on the efficacy of sequential second-generation ALK inhibitors are being generated,&rdquo; said Lyudmila A. Bazhenova, MD, a professor of medicine at University of California, San Diego Health. During her presentation at the 14th Annual New Orleans Summer Cancer Meeting, she posed the question &ldquo;Will a second-generation ALK inhibitor work after another second-generation agent?&rdquo;

The exact mechanisms of resistance to these agents are not yet fully understood, Bazhenova said, but encouraging data are illuminating strategies that may help extend survival in patients with these tumors.

Second-Generation Agents

In the phase II ASCEND-9 trial, the second-generation ALK inhibitor ceritinib (Zykadia) was assessed for response in patients withALK-rearranged metastatic NSCLC (n = 20) who had previously received alectinib (Alecensa) in the frontline or later. The agent produced an overall response rate (ORR) of 25% (95% CI, 8.7%-49.1%), with 1 complete response. The disease control rate (DCR) was 70% (95% CI; 45.7%-88.1%).2

At a median follow-up of 11.6 months, the median progression-free (PFS) survival was 3.7 months (95% CI, 1.9-5.3); median time to response, 1.8 months (range, 1.8-2.0); and median duration of response, 6.3 months (95% CI; 3.5-9.2).2

&ldquo;Based on these findings, ceritinib could be considered as one of the treatment options for patients withALK-positive NSCLC who progressed on alectinib,&rdquo; concluded the study investigators, led by Toyoaki Hida, MD, PhD.

Unlike ceritinib and alectinib, which both have indications as possible frontline therapy in patients withALK-rearranged tumors, approval for the ALK inhibitor brigatinib (Alunbrig) is limited to patients who received the first-generation agent crizotinib (Xalkori) and became intolerant or experienced progressive disease during therapy. Two poster presentations at the 2019 American Society of Clinical Oncology Annual Meeting looked at the efficacy of brigatinib following prior therapy with &ge;1 ALK inhibitor (TABLE).

In the retrospective BRIGALK trial, 104 patients receiving brigatinib following &ge;2 prior ALK inhibitors were assessed for efficacy. The primary endpoint was PFS from the initiation of brigatinib; secondary endpoints included ORR and overall survival (OS).3

In 91 evaluable patients, the ORR was 50% and the DCR was 78.2%. The median PFS was 6.6 months (95% CI, 4.8-9.9) and the OS was 75.3 months (95% CI, 38.2-174.6).

Prior ALK inhibitors in patients on the trial included crizotinib, alectinib, and ceritinib, with a small number of patients also receiving the third-generation agent lorlatinib (Lorbrena).

&ldquo;This study confirms the efficacy of brigatinib in a cohort of patients heavily pretreated forALK-positive advanced NSCLC,&rdquo; the study investigators, led by Renaud Descourt, MD, PhD, wrote in their presentation.

In preliminary data from a phase II trial of brigatinib in 20 patients with &ge;1 prior ALK inhibitor, there was an ORR of 40% and a median PFS in the overall cohort of 6.4 months (95% CI, 4.6-not evaluable). Based on these results, the trial was expanded to include 2 additional cohorts: one for patients with disease progression after frontline alectinib and another for a dose-escalation strategy of brigatinib to 240 mg daily in patients with disease progression on brigatinib at 180 mg daily and acceptable toxicity.4

Evaluating Lorlatinib&rsquo;s Efficacy Across Prior Therapies

The brain-penetrant, third-generation ALK inhibitor lorlatinib (Lorbrena) is active against most known resistance mutations that can develop during therapy with crizotinib and second-generation agents.

In a phase II trial of patients withALK- orROS1-positive advanced or metastatic NSCLC, lorlatinib induced a response in 69.5%. In patients who had previously received crizotinib, the ORR was 69.5%. In those with &ge;1 ALK inhibitors, the ORR was 47%.5

An analysis of the data showed that having a detectable baselineALKmutation by tissue or plasma following treatment with a second-generation ALK inhibitor was a significant predictor of lorlatinib response. Patients who were positive for the mutation had an ORR of 62% versus 32% among mutation-negative patients. This contrasts with patients who had received crizotinib as their most recent therapy—their corresponding rates of response were 73% and 75%.

&ldquo;With new data on the differential efficacy of lorlatinib in patients with and without [detectable] mutations, postprogression biopsies might become more important,&rdquo; Bazhenova said.


  1. Bazhenova LA. ALK mutant NSCLC. Presented at: 14th Annual New Orleans Summer Cancer Meeting; July 19-21, 2019; New Orleans, LA.
  2. Hida T, Seto T, Horinouchi H, et al. Phase II study of ceritinib in alectinib-pretreated patients with anaplastic lymphoma kinase-rearranged metastatic non- small-cell lung cancer in Japan: ASCEND-9.Cancer Sci. 2018;109(9):2863-2872. doi: 10.1111/cas.13721.
  3. Descourt R, Perol M, Rousseau-Bussac G, et al. Brigatinib in pretreated patients with ALK-positive advanced NSCLC.J Clin Oncol. 2019;37(suppl 15; abstr 9045). doi:10.1200/JCO.2019.37.15_suppl.9045.
  4. Stinchcombe T, Doebele RC, Wang XF, Gerber DE, Horn L, Camidge DR. Preliminary results of single arm phase 2 trial of brigatinib in patients (pts) with progression disease (PD) after next-generation (NG) anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) inALK+ non-small cell lung cancer (NSCLC).J Clin Oncol. 2019;37(suppl 15; abstr 9027). doi: 10.1200/JCO.2019.37.15_suppl.9.
  5. Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study.Lancet. 2018;19(12):1654-1667. doi: 10.1016/S1470-2045(18)30649-1.
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