Levy Compares Trials of ALK-Targeted Therapy for Patients With Metastatic NSCLC

Benjamin Philip Levy, MD

Associate Professor of Oncology

Clinical Director of Medical Oncology

Johns Hopkins Sidney Kimmel Cancer Center

Sibley Memorial Hospital

Washington, DC

Targeted OncologyTM: What systemic therapy are you most likely to recommend for patients with ALK-rearranged metastatic NSCLC?

LEVY: The National Comprehensive Cancer Network guidelines have 3 first-line therapies in category 1: alectinib [Alecensa], brigatinib [Alunbrig], and lorlatinib [Lorbrena].¹ Useful in certain circumstances is crizotinib [Xalkori] and [another recommended therapy is] ceritinib [Zykadia], which I used once for a patient, but it was an awful experience.

How was the trial for the category 1 therapy alectinib designed? What were the results?

[There are 3 trials] that compare next-generation ALK TKIs [tyrosine kinase inhibitors] with crizotinib. Unfortunately, we do not have head-to-head comparisons between alectinib, brigatinib, [and] lorlatinib. Each of these drugs, however, has been compared with crizotinib in [its respective] trial because that was the standard. The ALEX trial [NCT02075840] was a phase 3 trial of alectinib vs crizotinib for patients with stage IV ALK-rearranged lung cancer who had measurable disease.^2,3 This was in a treatment-naïve setting.

These patients are living a long time. The 5-year overall survival [OS] rate is 62.5% in the alectinib arm [vs 45.5% with crizotinib].³ When I started, the median OS for all patients was 12 months. This underscores how important it is to identify the fusion. I know clinicians don’t see it a lot, but what a difference it makes if you can identify it and then deliver these drugs.

[In the 5-year follow-up study, approximately] one-third of patients with central nervous system [CNS] metastases who were on alectinib at 4 years had not progressed. [Patients with] brain metastases lived 3 to 6 months on average before this. [Approximately] half the patients without CNS metastases at 4 years [had] not progressed on alectinib. So it’s remarkable. The bottom line is [that] alectinib outperformed crizotinib in every single patient population, minus the active smoker, which had small numbers [HR, 1.97; 95% CI, 0.38- 10.20; P = .547]. But these are the first data we had that showed alectinib had a clear signal in the brain.

Please discuss the data from the ALTA-1L (NCT02737501) trial of brigatinib vs crizotinib.

The [main] difference between this study and the ALEX study is that this study allowed prior chemotherapy. Most patients were treatment naïve, but some had prior chemotherapy. They were allowed a crossover. If they got crizotinib, they could get brigatinib afterward if they had disease progression on crizotinib.⁴

The blind, independent central review assessment of progression-free survival [PFS] showed, not surprisingly, an improvement with brigatinib [3-year PFS, 24 months with brigatinib vs 11.1 months with crizotinib (HR, 0.48; 95% CI, 0.35-0.66)].⁴ Similar to the ALEX study, the subgroup analysis showed that everyone did well. I think the signal that stood out was the 81 patients who had brain metastases in both the brigatinib arm [n = 40] and crizotinib arm [n = 41]. That was a big hazard ratio: 0.25 for those with brain metastases [95% CI, 0.14-0.46]. A lot of us thought brigatinib may be the more active drug in the CNS vs alectinib. We don’t have cross-trial comparisons, but it seemed like there was a little more robust activity.

If you looked at the intracranial PFS, which is the progression within the brain, in patients with any brain metastases at baseline, the hazard ratio was 0.29 for any progression in the brain⁴ : a 71% chance at any time that you would not experience further progression in the brain with brigatinib vs crizotinib. In those [who] didn’t have brain metastases, there was a hazard ratio of 0.44.

A lot of us began to think, at least in lung cancer, maybe brigatinib had a better signal, and maybe if patients have brain metastases we should use brigatinib rather than alectinib. I don’t think that panned out because it was a cross-trial comparison, and a lot of us were already familiar with alectinib. We’re all creatures of habit; we like to go with what we know.

How did the patients in the ALTA-1L trial respond to treatment?

The objective response rate [ORR] of the overall patient population for brigatinib was 74% vs 62% with crizotinib [odds ratio (OR), 1.73; 95% CI, 1.04-2.88; P = .0342].⁴ These response rates were durable [with a 2-year probability of maintaining response at 51% (95% CI, 40%-61%) in the brigatinib arm and 30% (95% CI, 10%-42%) in the crizotinib arm.] The intracranial response showed 66% of patients with any brain metastases at baseline vs only 16% in the crizotinib arm [OR, 11.75; 95% CI, 4.19-32.91; P < .001].⁵

The bottom line is brigatinib had a good ORR in the brain. It was probably just as good as alectinib, but it seemed like if you looked at the data more in detail, brigatinib may have had an edge.

[Results from] this study did not show a survival advantage because there was a tremendous amount of crossover.^4,5

Half of patients [who] were in the crizotinib arm crossed over to brigatinib, so [the results] didn’t really show a benefit in survival.

What were the design and results of the CROWN trial?

Finally, lorlatinib in [the CROWN study] [NCT03052608] came out. Lorlatinib started as a second-line drug for ALK-rearranged lung cancer.⁶ It was a great option. In this study, lorlatinib, [like alectinib and brigatinib in] ALEX and ALTA-1L, [respectively], went head-to-head with crizotinib.

There was no crossover allowed between the treatment arms. This was a treatment-naïve population [with] stage IV ALK-rearranged lung cancer, and CNS metastases were allowed. [When comparing] ALTA-1L and ALEX and the CROWN studies, CROWN had the best PFS hazard ratio, meaning the smallest number [HR, 0.27; 95% CI, 0.184-0.388]. There was a 73% chance at any time of not progressing on lorlatinib vs crizotinib. This is the most robust hazard ratio we’ve seen when comparing it with a similar control arm of crizotinib.

If you look at the ORR, it was 77.2% with lorlatinib vs 58.5% with crizotinib [OR, 2.25; 95% CI, 1.35-3.89], and responses were durable. The tumor response rates had a median time to objective response that was [small] in both arms [1.8 months]. But the PFS Kaplan Meier curves split quickly. [If we look at] the OS, the hazard ratio was 0.72 with lorlatinib vs crizotinib [95% CI, 0.41-1.25], and crossover wasn’t allowed.

How did lorlatinib affect patients with CNS metastases?

Here’s where things get interesting with the brain metastases data. If you look at patients with measurable or nonmeasurable brain metastases…who were given lorlatinib—and there were only 38 patients—23 of those 38 had a complete response, which is incredible.

So 61% vs 15% [had a complete response with lorlatinib vs crizotinib]. The ORR was 66% in the lorlatinib arm and 20% in the crizotinib arm, so it’s remarkable to see this type of CNS activity in the brain.⁶ [There was an updated analysis on the CROWN trial] looking at patients given lorlatinib or crizotinib with no brain metastases or with brain metastases [who] were presenting at the time of the study enrollment.⁷

At the 3-year mark, 98% [of] patients [with] no brain metastases, the most common patient [group] enrolled in this study, were still free of brain metastases at 3 years. We know that ALK has a tropism for the brain, and to see something like this is incredible.

Of those patients who did have brain metastases at 3 years, 71% of patients [on lorlatinib had an intracranial complete response vs 8% on crizotinib]. The question is, does this drug have more activity in the brain than brigatinib or alectinib? We don’t have head-to-head comparisons.

What adverse reactions are you most concerned about with each of these therapies?

These drugs do have toxicities. With alectinib, there are liver [problems], edema, and increased weight.⁸ With brigatinib, maybe some creatine phosphokinase abnormalities, diarrhea, and nausea.⁹ Then [with] lorlatinib, there are CNS events, mood effects, and hyperlipidemia.¹⁰

When I talk to the community and other lung cancer physicians, we have a tough time understanding how to identify these. I don’t know [whether] anyone has seen CNS [events] or mood effect[s] from lorlatinib, but [they’re] interesting to manage and look at. We just have to be careful.

REFERENCES

1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 1.2023. Accessed January 23, 2023. https://bit.ly/3HudboI

2. Peters S, Camidge DR, Shaw AT, et al; ALEX Trial Investigators. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377(9):829-838. doi:10.1056/NEJMoa1704795

3. Mok T, Camidge DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol. 2020;31(8):1056-1064. doi:10.1016/j.annonc.2020.04.478

4. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK inhibitor-naive advanced ALK-positive NSCLC: final results of phase 3 ALTA-1L trial. J Thorac Oncol. 2021;16(12):2091-2108. doi:10.1016/j.jtho.2021.07.035

5. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer: second interim analysis of the phase III ALTA-1L trial. J Clin Oncol. 2020;38(31):3592-3603. doi:10.1200/JCO.20.00505

6. Shaw AT, Bauer TM, de Marinis F, et al; CROWN Trial Investigators. Firstline lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(21):2018-2029. doi:10.1056/NEJMoa2027187

7. Three year follow-up data from phase 3 CROWN trial of Pfizer’s LORBRENA (lorlatinib) confirm prolonged progression-free survival in first-line ALK-positive advanced lung cancer. News release. Pfizer. April 8, 2022. Accessed January 25, 2023. https://bit.ly/3JeMLc0

8. Alecensa. Prescribing information. Genentech; 2021. Accessed January 23, 2023. https://bit.ly/2lP6Nky

9. Alunbrig. Prescribing information. Takeda Pharmaceuticals; 2022. Accessed January 23, 2023. https://bit.ly/2Fia1W0 10. Lorbrena. Prescribing information. Pfizer; 2021. Accessed January 23, 2023. https://bit.ly/3kYa5AI