Targeted oncology: What do the National Comprehensive Cancer Network (NCCN) guidelines recommend for the treatment of patients with cancer-positive non-small cell lung cancer? alk Gene rearrangement?
Yasir Y. Elamin, MD: The NCCN Guidelines distinguish between patients who: alk Genetic rearrangement discovered in previous first-line systemic therapy, preferred 3-drug is alectinib [Alencsa]brigatinib [Alunbrig]lorlatinib [Lorbrena],versus alk The gene rearrangement was discovered while the patient was undergoing chemotherapy.1 NCCN then gives you the option of continuing systemic therapy, including maintenance therapy, or discontinuing it and switching to an ALK tyrosine kinase inhibitor. [TKI].1 I think most of us, even if we do one cycle of chemotherapy, we tend to discontinue and switch to an ALK TKI once a fusion is discovered.
What data led to the approval of brigatinib in this setting?
Oncologists' first attempt [on the NCCN panel] you're probably used to it [recommend] Brigatinib is in the ALTA-1L trial [NCT02737501].2 In this trial, TKI-naive patients alk– Positive lung cancer randomly assigned to crizotinib [Xalkori] This was the standard of care at the time versus brigatinib. Brigatinib is given in the usual way, 90 mg for 7 days, followed by 180 mg a week later. This takes into account early pulmonary toxicity. Treatment in this trial was continued until disease progression or unacceptable toxicity, and the primary endpoint was progression-free survival. [PFS] By blinded independent review measured by RECIST [criteria].
As you might expect, most patients were nonsmokers, the majority had stage IV disease, and the majority had adenocarcinoma.2 Approximately one-third of patients in each group had brain metastases at baseline. [This is] This is reflective of typical lung cancer patients, who typically present with stage IV disease, and these patients, who are nonsmokers, frequently have brain metastases.
What kind of efficacy was found in this trial, and how did patients with brain metastases respond?
Confirmed objective response rate [ORR] It was 74% in the brigatinib group versus 62% in the crizotinib group.3 When you look at patients with measurable brain metastases at baseline, the numbers are small: only 18 in the brigatinib group and 23 in the crizotinib group. [but] ORR was 78% in the brigatinib group and 26% in the crizotinib group. An independent review of baseline brain metastases found that the ORR for brigatinib was 66% compared to 16% for crizotinib, indicating that these next-generation ALK inhibitors It confirms what we all know that if you do that, the intracranial efficacy is better. Crizotinib. Five of 18 patients in the brigatinib group had a complete intracranial response.
with therapeutic intent [ITT] Investigator-assessed median PFS was 30 months in the brigatinib group compared to 9 months in the crizotinib group.Four A blinded, independent review found that it was 2 years for brigatinib and 11 months for crizotinib. The investigator-assessed HR was 0.43, whereas the independent review-assessed HR was 0.48.
[In the ITT population]intracranial PFS was 44 months in the brigatinib arm, HR 0.44. [95% CI, 0.30-0.65; log-rank P < .0001], similar to those seen extracranially. Intracranial PFS for patients with brain metastases was 24 months, very similar to that observed extracranially, with a hazard ratio of 0.29. [95% CI, 0.17-0.51; P < .0001].
In the final overall survival [OS] data, ITT population is 2 [Kaplan-Meier] curves overlap [HR, 0.81; 95% CI, 0.53-1.22; log-rank P =.305]However, the 4-year survival rate for the brigatinib group was 66%, compared with 60% for the crizotinib group. Interestingly, in patients with brain metastases, a clear separation between the curves was seen, confirming the superiority of brigatinib over crizotinib in terms of brain efficacy, and this early separation between the curves may indicate that these This suggests that many of the patients were lost to the cause. This reinforces the importance of having drugs with potent intracranial activity to treat these patients.
What is the toxicity profile of brigatinib based on this study?
I would like to focus on severe toxicity.In the brigatinib group, 70% of patients experienced grade 3 or 4 toxicity [vs 56% with crizotinib]Next, from the perspective of adverse events [AE] Symptoms leading to treatment discontinuation were seen in 13% of patients [vs 9%, respectively]44% of patients required dose reduction. [vs 25%, respectively].Four Some of the common AEs we observed were increases in creatine phosphokinase and lipase, and severe hypertension was also observed in 14% of patients treated with brigatinib. [vs 4% with crizotinib].
in spite of [the fact that] Although early lung toxicity was an issue in some patients, overall it was not a major limitation of the drug, and the overall incidence of pneumonia was low. It turns out that if these patients make it through the first week without lung toxicity, they can continue taking the drug for months or years without major problems.
References:
1.NCCN. Clinical practice guidelines in oncology. Non-small cell lung cancer, version 5.2024. Accessed April 25, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
2. Camidge DR, Kim HR, Ahn MJ, et al. Comparison of brigatinib and crizotinib in ALK-positive non-small cell lung cancer. N English J Medicine. 2018;379(21):2027-2039. doi:10.1056/NEJMoa1810171
3. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in advanced ALK inhibitor-naïve ALK-positive non-small cell lung cancer: second interim analysis of the phase III ALTA-1L trial. J Clin Oncor. 2020;38(31):3592-3603. doi:10.1200/JCO.20.00505
4. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK inhibitor-naive advanced ALK-positive NSCLC: Final results from the phase 3 ALTA-1L trial. J Solak Oncor. 2021;16(12):2091-2108. doi:10.1016/j.jtho.2021.07.035