Combinatorial therapy is a safe and durable treatment option in ALK-rearranged non-small cell lung cancer with an acquired MET exon 14 skipping mutation mediated resistance to alectinib: a case report

Introduction

Anaplastic lymphoma kinase (ALK)-rearrangements occur in approximately 5% of non-small cell lung cancer (NSCLC) (1). NSCLC harboring ALK rearrangements are highly sensitive to ALK inhibitors demonstrating high and rapid response rates. Despite these robust responses, patients inevitably develop acquired resistance leading to clinical relapse. These resistance mechanisms can be classified into ALK dependent alterations and ALK independent alterations with the latter being less well characterized. ALK dependent mechanisms include ALK secondary mutations or amplification in which dependency on ALK signaling persists. ALK independent mechanisms include the activation of bypass pathways including EGFR, KIT, HER, MET, SRC, and IGF-1R pathways which result in the reactivation of downstream effectors leading to tumor cell proliferation and survival.

Identifying these resistance mechanisms is important in treating patients who acquire ALK resistance as ALK dependent alterations may indicate persistent dependence on ALK signaling. In these cases, alternative ALK tyrosine kinase inhibitors (TKIs) may be potentially effective therapeutic options. On the other hand, ALK independent resistance mechanisms may necessitate an alternative therapeutic approach. Here we report a case of an acquired mesenchymal epithelial transition factor (MET) exon 14 skipping (METex14) mutation mediated resistance to alectinib in a patient with Stage IV ALK-rearranged lung adenocarcinoma successfully treated with combination therapy of capmatinib and alectinib. We present this case in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-613/rc).

Case presentation

A 72-year-old male with a 2-pack year smoking history and end-stage renal disease (ESRD) on hemodialysis presented to the emergency department with two days of chest tightness. A computed tomography (CT) scan revealed a right unilateral pleural effusion and a 1.5 cm heterogenous mass in the left lung apex. Pleural fluid cytology was significant for an ALK-positive metastatic lung adenocarcinoma by immunohistochemistry. Programmed death-ligand 1 (PD-L1) staining was negative. Next-generation sequencing (NGS) was performed on the pleural fluid cytoblock using the Oncomine Focus Assay targeted panel, which confirmed an echinoderm microtubule-associated protein 4 (EML4)-ALK gene fusion. No other relevant alterations, including MET amplification or METex14 mutation, were identified (Table S1). A liquid biopsy using the FoundationOne Liquid CDx assay was also performed which did not identify the ALK rearrangement or MET mutations (Table 1). The patient was treated with alectinib 600 mg twice daily. Interval imaging at 5 months demonstrated overall stable disease. The patient had clinical improvement in his symptoms including shortness of breath and chest tightness. He tolerated alectinib well without significant adverse events. However, CT imaging at 7 months demonstrated interval growth of the left apical lung nodule and a new right apical nodule. Patient declined a tissue biopsy at the time of progression. A liquid biopsy using the FoundationOne Liquid CDx assay was performed, which revealed a MET exon 14 skip mutation (3028G>A). The ALK rearrangement was not identified on the liquid biopsy (Table 1).

Prior to the development of TKIs, pemetrexed-based chemotherapy was the standard front-line therapy for ALK-positive NSCLC as these patients have been shown to derive greater benefit from pemetrexed with longer progression-free survival when compared to other oncogene-addicted NSCLC, including EGFR and KRAS mutations (2). However, targeted therapies have replaced chemotherapy-based regimens for both ALK-positive and MET-positive NSCLC as standard front-line therapy leading to significant improvements in progression-free survival and overall survival along with high response rates and milder toxicities. Capmatinib has demonstrated high response rates in both treated (41%) and treatment-naive (68%) patients with NSCLC with a METex14 mutation. These patients also demonstrated durable responses with a median duration response of 9.7 and 12.6 months in treated and treatment-naïve patients, respectively (3). As a result, the decision was made to initiate capmatinib 400 mg twice daily in combination with alectinib 600 mg twice daily. Interval imaging at one month demonstrated significant response with decreased size of the left apical nodule and improved mediastinal and left supraclavicular lymphadenopathy (Figure 1). Patient remains on therapy and continues to demonstrate overall stable disease at 15 months (Figure 2).

Figure 1 Imaging at time of progression on alectinib (A) and on-treatment with dual therapy of capmatinib and alectinib (B) of a 72-year-old male with an acquired MET exon 14 skipping mutation mediated resistance to alectinib. MET, mesenchymal epithelial transition factor.

Figure 2 Patient timeline. Green represents the time of diagnosis. Orange represents the time of progression. Yellow represents prior and current treatment regimens. 2023-08 represents the last timepoint assessed during the case study. EML4, echinoderm microtubule-associated protein 4; ALK, anaplastic lymphoma kinase; MET, mesenchymal epithelial transition factor.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Second-generation ALK TKIs have significantly improved survival outcomes in NSCLC, especially in patients whose tumors harbor EML4-ALK translocations. In a study that compared alectinib with crizitonib, alectinib demonstrated a median progression free survival of 34.8 months in previously untreated, advanced ALK-positive NSCLC (4). However, the clinical impact of ALK-inhibitors is limited due to the inevitable development of resistance mechanisms. The emergence of these resistance mechanisms has made treatment decisions increasingly more complex.

Our patient demonstrated an initially durable response with overall stable disease radiographically on alectinib and had improvement in symptoms of shortness of breath and chest tightness. However, our patient eventually developed progression of disease at 7 months. Plasma NGS of a liquid biopsy at the time of progression revealed an acquired METex14 mutation (3028G>A). METex14 is present in about 3–4% of lung adenocarcinomas (4,5). Crizotinib, which is a multi-kinase inhibitor approved for ALK- or ROS1-rearranged NSCLC, has been shown to have activity against MET kinase (6). Thus, crizotinib may be an effective treatment strategy for ALK rearranged NSCLC with MET mediated resistance. In a case report by Daniel et al., crizotinib led to a partial response with a 35% reduction in distant metastases that was maintained for 3 months in an ALK rearranged NSCLC with an acquired METex14 mediated resistance to alectinib (7). Additional studies have shown that patients with acquired MET-driven resistance such as MET amplification after treatment with next-generation ALK inhibitors may benefit from therapies that target both ALK and MET (8,9).

The development of highly specific MET inhibitors such as tepotinib and capmatinib have demonstrated both robust responses and tolerable safety profiles in patients with METex14 NSCLC (3,10). These TKIs have also been shown to have antitumor activity in patients with MET-amplified NSCLC. Concurrent MET amplification has been reported in 15–21% of METex14 positive NSCLC (5,11,12). Both liquid biopsy and tissue-based NGS in our patient did not reveal a concurrent MET amplification. Because of the high response rates, we elected to start the patient on capmatinib. The decision was also made to continue alectinib as we believe the clonal driver mutation was the EML4-ALK fusion gene mutation and the METex14 was the subclonal resistance mutation. This combinatorial therapy regimen led to a durable response in our patient.

However, successful combination therapy must not only demonstrate superior efficacy but must also demonstrate tolerable safety profiles. Combination therapies are often limited by increased risk for adverse events as was the case with osmertinib and durvalumab combination therapy in EGFR-mutant lung cancer, which led to a ten-fold increase in interstitial lung disease compared to osimertinib or durvalumab monotherapy (13). In a prior study evaluating the efficacy and tolerability of ALK/MET combination therapies in ALK-rearranged NSCLC, all three patients who were treated with a combination of alectinib and capmatinib experienced treatment related adverse events. Two of these patients required dose interruptions for grade 2 peripheral edema and persistent grade 1 pyrexia. All three patients developed grade 2 peripheral edema requiring initiation of diuretics. Other toxicities included grade 1 transaminase level elevation and grade 1 muscle and grade 1 joint adverse events (14). Our patient experienced lower extremity edema. However, this was not dose limiting potentially due to ongoing dialysis for his ESRD. Our patient had no other significant adverse events with combination therapy of alectinib and capmatinib. Further case reports have also shown success in treating EGFR-mutant NSCLC with acquired MET mediated resistance with combinatorial therapy of EGFR-TKI and MET inhibitors (15,16). Thus, in patients who acquire resistance after initial TKI therapy, combinatorial therapy may provide a promising effective and safe therapy option to overcome ALK TKI resistance.

In addition, our case report demonstrated the safety and efficacy of alectinib and capmatinib in ESRD patients on dialysis. This may be partly explained by the fact that alectinib and capmatinib are both metabolized by cytochrome P450 3A4 into their active metabolites, which are removed by the biliary system. In addition, both alectinib and capmatinib and their metabolites are bound to human plasma protein which may prevent their elimination by the dialysis membrane. In a case report evaluating the pharmacokinetics of alectinib in a patient with advanced lung adenocarcinoma undergoing hemodialysis and receiving the standard full dose of alectinib, the maximal observed plasma concentration of alectinib was shown to be similar to those in non-ESRD patients (17). Dose adjustments in either alectinib or capmatinib were not required in our patient to achieve a durable response without significant adverse events. However, further studies are needed to evaluate the pharmacokinetics and assess the long-term safety and efficacy of both alectinib and capmatinib in patients with renal impairments.

The initial ALK rearrangement was not identified from the liquid biopsy NGS at the time of progression. The ALK rearrangement may not have been detected as the patient was receiving alectinib at the time of the liquid biopsy collection. Moreover, the low sensitivity and risk of false-negative tests with liquid biopsy NGS have limited their clinical impact leading to recommendations by the United States Food and Drug Administration for tumor biopsy-based NGS in patients with negative test results on liquid biopsy NGS to confirm mutational status. A limitation of this case report is that our patient did not undergo repeat tissue biopsy at time of progression. It is unlikely, although possible, that the METex14 clone represents a second primary lung cancer.

Conclusions

Patients should undergo resequencing at time of progression to identify potential actionable mutation mediated resistance mechanisms. To our knowledge this is the first reported case of dual alectinib and capmatinib therapy in a patient with ALK rearranged NSCLC and METex14 mediated primary resistance. Combinatorial therapy remains a promising treatment option for patients who develop acquired resistance mechanisms after TKI therapy. Moreover, up-front treatment with multikinase inhibitors and combination therapy that co-target ALK with MET, EGFR, and KIT may lead to a synergistic and more durable response and suppression of TKI resistance than monotherapy alone. Further prospective studies are needed in this setting to better understand the efficacy and safety profile of combinatorial therapies to improve outcomes in NSCLC.

Acknowledgments

The authors would like to express their gratitude to the pharmacists, clinicians, nurses, and staff who contributed to the care of this patient.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-613/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-613/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-613/coif). J.S. declares consultant and advisory roles in AstraZeneca, Abbvie, Genentech, Janssen, Jazz, Loxo Lilly, Mirati, Navire, Pfizer, Regeneron, Sanofi Genzyme, Takeda; and receives Research Funding (Institutional) from Janssen and Boehringer Ingelheim. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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