Activity of Brigatinib in the Setting of Alectinib Resistance Mediated by ALK I1171S in ALK-Rearranged Lung Cancer

Introduction

Multiple ALK receptor tyrosine kinase (ALK) inhibitors have upended the evidence-based management of advanced NSCLC over the last half decade.¹ Crizotinib was the first ALK inhibitor to reach regulatory approval in the first-line management of ALK receptor tyrosine kinase gene (ALK)-rearranged NSCLC, and the next-generation ALK inhibitors ceritinib, alectinib, and brigatinib are highly active after intracranial or systemic progression during crizotinib therapy.¹ More recently, alectinib improved outcomes in the treatment-naive setting in comparison with crizotinib, and ceritinib was shown to be superior to cytotoxic therapies in the same setting.¹ The management of ALK-rearranged tumors that become biologically resistant to next-generation ALK inhibitors continues to be undefined, but knowledge of the mechanism of resistance may allow for sequencing of approved or in-development ALK inhibitors.^2–5 Here, we present what, to the best of our knowledge, is the first reported case in which alectinib resistance mediated by the ALK I1171S mutation was overcome by brigatinib.

Case Presentation

A 57-year-old white woman with a history of never smoking presented with advanced lung adenocarcinoma and brain metastases. The tumor was found to harbor an ALK rearrangement: echinoderm microtubule associated protein like 4 (EML4)-ALK E6;A19. Initial therapy consisted of whole brain radiotherapy and carboplatin/ pemetrexed followed by maintenance pemetrexed until progression 14 months afterward. Administration of crizotinib, 250 mg twice daily, was commenced and elicited a response that lasted 19 months before systemic and intracranial progression. A lymph node biopsy did not indicate ALK resistance mutations. At that point, alectinib (initially at 600 mg twice daily, but the dose was reduced on account of asymptomatic liver toxicity) was introduced and led to a systemic and intracranial response. Alectinib was continued for the subsequent 24 months, at which time progressive liver metastases were noted (Fig. 1A) without intrathoracic or brain progression. A liquid biopsy using comprehensive genomic profiling revealed the known ALK rearrangement, an ALK I1171S mutation (0.24% allele frequency), and tumor protein 53 gene (TP53) V218G mutation (0.50% allele frequency) (Fig. 1A). On the basis of preclinical data indicating that ALK I1171X mutants could be overcome by the approved inhibitors brigatinib or ceritinib (Table 1), administration of brigatinib was started at its usual 90 mg daily dose for a week and then escalated to 180 mg daily, which led to a partial radiographic response with regression of liver lesions (Fig. 1B) and maintained control of the intrathoracic and brain tumor burden. Therapy was associated with normalization of the liver enzyme profile with no additional adverse events. The response has been maintained during the 9 months of follow-up.

Figure 1.

Computed tomography images illustrating disease response. (A) Red circles highlight liver metastases at baseline. A liquid biopsy using the commercially available test FoundationACT (Foundation Medicine, Cambridge, MA) was used; a tumor biopsy was not obtained. (B) After 3 months of brigatinib therapy, the hepatic metastases (red circles) decreased significantly in size in a manner consistent with a partial response by the Response Evaluation Criteria in Solid Tumors version 1.1. Abbreviations: EML4-ALK, echinoderm microtubule associated protein like 4 gene (EML4) and ALK receptor tyrosine kinase gene (ALK) rearrangement; TP53, tumor protein p53 gene.

Table 1.

Pattern of Preclinical and Clinical Sensitivity of Different ALK I1171X Mutations in the Context of EML4-ALK Rearrangement in Lung Cancer

ALK Inhibitor	Alectinib	Ceritinib	Brigatinib	Crizotinib	Lorlatinib
Approval Status (Line of Therapy)	Approved (First-/Second-Line)	Approved (First-/Second-Line)	Approved (Second-Line)	Approved (First-Line)	In Development (Second-/Third-Line)
EML4-ALK + ALK I1171N
In vitro sensitivity (mean IC50 nM)	Resistant (397.7 nM)	Sensitive (8.2 nM)	Sensitive (26.1 nM)	Resistant (130.1 nM)	Sensitive (49.0 nM)
Presumed response to clinical dosing	Resistance	Response	Response	Resistance	Response
Patient response, reference	NA	Yes5	Not reported	NA	Not reported
EML4-ALK + ALK I1171S
In vitro sensitivity (mean IC50, nM)	Resistant (177.0 nM)	Sensitive (3.8 nM)	Sensitive (17.8 nM)	Resistant (94.1 nM)	Sensitive (30.4 nM)
Presumed response to clinical dosing	Resistance	Response	Response	Resistance	Response
Patient response, reference	NA	Not reported	Yes, current report	NA	Not reported
EML4-ALK + ALK I1171T
In vitro sensitivity (mean IC50, nM)	Resistant (33.6–80.0 nM)	Sensitive (1.7–4.3 nM)	Sensitive (6.1 nM)	Resistant (51.4–236.0 nM)	Sensitive (11.5 nM)
Presumed response to clinical dosing	Resistance	Response	Response	Resistance	Response
Patient response, reference	NA	Yes4	Not reported	NA	Not reported

All preclinical in vitro sensitivities were based on the published data for cellular ALK phosphorylation in Ba/F3 cells outside ALK I1171T from Gainor et al.³; the range provided in Katayama et al.⁴ was also used.

ALK, ALK receptor tyrosine kinase gene; EML4, echinoderm microtubule associated protein like 4 gene; IC₅₀, 50% inhibitory concentration; NA, nonapplicable; nM, nanomolar.

Discussion

The mechanisms of systemic biologic resistance to alectinib and ceritinib—the two next-generation ALK inhibitors currently approved for use in the first-line setting—seem to be predominantly mediated by heterogeneous ALK kinase domain mutations that selectively alter the pattern of response to other ALK inhibitors.^3,4 The clinical use of tissue versus liquid biopsies to detect such mutations continues to evolve, and tumor-derived plasma cell-free DNA genotyping techniques (such as the one used in our case) seem to have clinical sensitivities that exceed 60%.⁶ The ALK G1202R mutation is the most common; it is cross-resistant to alectinib and ceritinib but responsive to the potent ALK inhibitor lorlatinib, which was designed to have activity against ALK kinase domain resistance mutations plus central nervous system penetration and is undergoing the final stages of regulatory approval.^2,3 Interestingly, some mutations are specific to alectinib or ceritinib³ (Table 1). ALK I1171X mutations seem to preferentially be alectinib resistance mutations, and preclinical models of EML4-ALK plus ALK I1171N/S/T (Table 1) proteins indicate that ceritinib, brigatinib, or lorlatinib have putative sensitivity against them.^3,4 To date, only ceritinib had been reported by other groups to induce clinical responses in ALK I1171X-bearing alectinib-resistant tumors.^4,5 Our case report of clinical response to brigatinib in ALK I1171S-positive lung cancer highlights the rapidly evolving management of advanced ALK-rearranged tumors and the role of clinically available liquid/tissue rebiopsies in guiding the sequencing of available or in-development ALK inhibitors.