A Patient With Anaplastic Lymphoma Kinase–Positive Non–Small Cell Lung Cancer With Development of Leptomeningeal Carcinomatosis While on Targeted Treatment With Crizotinib (2024)

NCCN: Continuing Education

Case Report

The patient is a 55-year-old Asian man with minimal smoking history (1 pack-year in the distant past), but a significant history of coronary artery disease with stent placement requiring maintenance with clopidogrel and aspirin. He presented with subacute cough, scant hemoptysis, worsening dyspnea on exertion, and night sweats. Chest radiograph after a trip to Asia revealed a lung mass in the right upper lobe. A palpable right supraclavicular lymph node was noted on examination, and biopsy results of this lymph node showed metastatic adenocarcinoma of a lung primary (CK7+, CK20-, TTF1+). The patient's tumor was negative for both KRAS and epidermal growth factor receptor (EGFR)–activating mutations. PET/CT showed the FDG-avid mass in the right upper lobe of the lung, and metastases to the bone, liver, and multiple lymph nodes. MRI of the brain was negative for intracranial disease.

The patient was initially treated with carboplatin and pemetrexed for 6 cycles followed by continuation maintenance pemetrexed for 17 cycles, until systemic progression was noted on CT scan with the development of a new thoracic spine bone lesion, and growth in lung, lymph node, and liver lesions. MRI of the brain at that time revealed an asymptomatic 9-mm brain metastasis that was treated with stereotactic radiotherapy.

The patient was then treated with erlotinib for 2 cycles but developed rapid disease progression. The patient was then placed briefly on docetaxel, but mucositis and neutropenia were dose-limiting. Anaplastic lymphoma kinase (ALK) fluorescence in situ hybridization (FISH) testing became commercially available at this time and the patient's tumor was found to be positive for an ALK translocation on break-apart FISH analysis. Crizotinib was initiated at 250 mg orally twice daily. The patient experienced a rapid partial response and symptomatic improvement, while working full-time and traveling. This continued for 10 months, but he then developed headache, confusion, nausea, and vomiting. An MRI of the brain revealed enhancement of the leptomeninges consistent with leptomeningeal carcinomatosis (LM), progressive brain metastases, and ventriculomegaly (Figure 1). An elevated opening pressure of 32 mm H₂O was noted on lumbar puncture, and cerebrospinal fluid (CSF) cytology was positive for metastatic adenocarcinoma. The patient's headache, nausea, and vomiting resolved shortly after lumbar puncture. He completed palliative whole-brain radiation to 30 Gy and received a ventriculoperitoneal shunt for increased intracranial pressure. Over the next several weeks he experienced a recurrence of neurologic symptoms, and was therefore transitioned to hospice care.

Discussion

The mainstay of first-line treatment in patients with metastatic non–small cell lung adenocarcinoma whose tumors do not harbor an EGFR-activating mutation or an ALK translocation is doublet chemotherapy (category 1). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer (NSCLC) currently list docetaxel, pacl*taxel, pemetrexed, vinorelbine, vinblastine, gemcitabine, etoposide, or albumin-bound pacl*taxel as proven effective agents when combined with carboplatin or cisplatin (to view the most recent version of these guidelines, visit NCCN. org).¹ In patients with nonsquamous histology, a first-line pemetrexed-based platinum doublet is frequently used based on phase III data showing an overall survival benefit of cisplatin/pemetrexed compared with cisplatin/gemcitabine in the first-line treatment of patients with metastatic lung cancer of nonsquamous histology.² Pemetrexed-containing first-line regimens are well tolerated by most patients and are associated with a much lower incidence of alopecia, neuropathy, and cytopenias than many other regimens. The additional benefit of adding bevacizumab to a platinum/pemetrexed backbone has been called into question by the recently presented Point Break Trial, which showed that overall survival was not increased with carboplatin/pemetrexed/bevacizumab followed by pemetrexed/bevacizumab maintenance compared with carboplatin/pacl*taxel and bevacizumab followed by bevacizumab maintenance.³ These results have lowered enthusiasm for a pemetrexed backbone when bevacizumab is used, although this is still a reasonable first-line treatment regimen.

Several retrospective analyses have shown a progression-free survival (PFS) benefit with pemetrexed compared with other chemotherapy agents in patients with ALK+ tumors, although prospective data are lacking.^4,5 This benefit may be from lower levels of thymidylate synthase seen in ALK+ NSCLC tumors.⁶ However, recently published data indicate that the preferential activity of pemetrexed may be associated with patients who have a history of light or never smoking rather than the presence of an ALK translocation, which in itself is also associated with a light-/never-smoking history.⁷ In the absence of significant toxicity or progression, the authors often continue pemetrexed after 4 to 6 cycles of bad break platinum/pemetrexed doublet chemotherapy, which is currently an NCCN category 1 recommendation. A statistically significant 2.9-month median improvement in overall survival (OS) after continuation maintenance with pemetrexed was observed in the phase III PARAMOUNT trial, as presented at the 2012 ASCO Annual Meeting.⁸

FDA approval of bevacizumab for NSCLC is based on the phase III ECOG 4599 clinical trial in which the addition of bevacizumab to a carboplatin and pacl*taxel backbone led to a statistically significant 2-month improvement in median overall survival in patients with nonsquamous NSCLC.⁹ One trial exclusion criterion was anticoagulation treatment, including regular use of 325 mg of aspirin or other inhibitors of platelet function. A modest increased risk of coronary thrombosis is also seen in patients on bevacizumab.¹⁰ In another large phase III randomized trial adding bevacizumab to cisplatin and gemcitabine, patients were allowed to stay on bevacizumab after the occurrence of venous thrombosis on trial. In total, 9% of patients in this study were on anticoagulant therapy with low-molecular-weight heparin or warfarin, and none experienced pulmonary hemorrhage.¹¹ In a large phase IV trial including bevacizumab, the incidence of grade 3 or greater bleeding on anticoagulation was 4%.¹² Several ongoing cooperative group clinical trials do not prohibit patients on anticoagulation from receiving bevacizumab.

Although this patient had only scant hemoptysis, he had active coronary artery disease (CAD) with 2 recent stent placements and was taking aspirin at 325 mg and clopidogrel, so the decision was made to forego bevacizumab. The authors' institution is comfortable treating patients with bevacizumab who are also receiving anticoagulation treatment based on the aforementioned data, but concern remains in patients with hemoptysis, active CAD, or other arterial thrombotic disease who are undergoing treatment with clopidogrel and other very potent direct

platelet inhibitors (ticlopidine, cilostazol).

Crizotinib, an oral ALK and MET small molecule tyrosine kinase inhibitor (TKI), was recently given accelerated approval by the FDA for patients with metastatic NSCLC harboring an ALK translocation as established by the companion FISH diagnostic test. Approval is expected based on the recently presented results of the phase III PROFILE 1007 (A Phase III Trial of Crizotinib Versus Standard of Care in Patients With Advanced Non–Small-Cell Lung Cancer With a Specific Alteration of the Anaplastic Lymphoma Kinase Gene) trial of crizotinib versus physician's choice of pemetrexed or docetaxel in the second-line setting and beyond. A PFS benefit (7.7 vs. 3 months) of crizotinib was noted, although no OS benefit was seen in an interim analysis, most likely because of the high degree of crossover (62%).¹³

FDA approval of crizotinib did not restrict its indication to the relapsed/refractory setting, and therefore crizotinib can be given in the first line, even though the clinical trials presented to date have evaluated it in patients whose disease has progressed after first-line chemotherapy. The current NCCN Guidelines list crizotinib with a default category 2A recommendation, rather than conventional platinum-based chemotherapy regimens, as first-line therapy in patients with metastatic NSCLC with FISH ALK+ tumors (to view the most recent version of these guidelines, visit NCCN.org).¹ The use of first-line crizotinib compared with cytotoxic chemotherapy is based on extrapolated data from the results of several large randomized phase III trials showing improvement in PFS but not OS with EGFR-targeted TKIs compared with platinum-doublet chemotherapy in patients with tumors harboring EGFR-activating mutations.^14–16 A randomized, phase III trial investigating first-line crizotinib versus carboplatin or cisplatin and pemetrexed in patients with FISH ALK+ tumors is ongoing (ClinicalTrials.gov identifier: NCT01639001).

This patient was diagnosed and started on first-line chemotherapy before ALK FISH testing was routinely available. He developed LM while on crizotinib. Isolated central nervous system (CNS) recurrence is a recognized phenomena in patients with ALK+ NSCLC treated with crizotinib.¹⁷ In patients with ALK+ tumors who have active CNS disease, the authors consider a pemetrexed-based regimen, preferably with platinum in patients who are not heavily pretreated, and bevacizumab if they do not otherwise have a contraindication. Several studies have demonstrated CNS activity of pemetrexed in NSCLC.^18,19 Although bevacizumab administration is contraindicated in untreated parenchymal brain metastases, sufficient evidence currently supports its use in patients with treated stable CNS disease.^20,21 Phase III data also support the use of bevacizumab in patients who develop radiation necrosis after brain irradiation for metastases.²² The authors have given bevacizumab in patients with active LM with some success and without significant toxicity. However, bevacizumab has not been sufficiently studied in LM and the role it will ultimately play in treating LM is not clear.

The mean CSF penetration of erlotinib is 5% to 10% of the systemic concentration.²³ Pulsed high-dose erlotinib has been used as a strategy to treat LM in patients with tumors harboring EGFR-activating mutations.^24,25 Crizotinib has some documented CSF penetration, although lower penetration compared with erlotinib.¹⁷ However, leptomeningeal involvement of cancer may lead to compromise of the blood-brain barrier with potentially increased CNS penetration. In a recent phase II study of crizotinib in patients with ALK+ tumors, 22% of patients with asymptomatic, nonirradiated brain metastases had a radiographic brain response.²⁶

After diagnosis of LM, this patient received whole-brain radiotherapy to 30 Gy and ventriculoperitoneal shunt placement with limited improvement in neurologic function. Analysis of LM outcomes is mainly from retrospective studies because prospective trials are limited for this uncommon complication. As in other malignancies, LM is a poor prognostic indicator in NSCLC.²⁷ Although whole-brain radiotherapy has not shown an overall survival benefit in a retrospective analysis, the authors consider palliative brain and possibly spinal radiation in their patients with LM for symptomatic relief.²⁷ If a patient with an ALK+ tumor develops isolated CNS or other metastases while on crizotinib, radiating the site of progression and restarting crizotinib may delay further progression based on a retrospective analysis.¹⁷ However, patients with LM were excluded from this analysis. No data have yet been published regarding the safety and efficacy of concurrent crizotinib and radiotherapy. Novel ALK inhibitors with potentially better CNS penetration are in development and will hopefully provide additional therapeutic options for patients such as the one described in this case report.²⁸

In patients with hydrocephalus and symptomatic improvement after large-volume lumbar puncture, as in this patient, the authors consider a ventriculoperitoneal shunt for palliative relief. Intrathecal chemotherapy with methotrexate or cytarabine or liposomal cytarabine or topotecan is also a treatment option they use infrequently. A recent single-institution retrospective case series noted prolonged survival in the small number of patients who received intrathecal chemotherapy, but this may be because of selection bias.²⁷

LM in NSCLC, as in other malignancies, remains challenging to treat. However, some limited evidence is mounting that outcomes may be improved in the modern treatment era, although many of the studies are retrospective and thus limited by multiple biases.²⁹ A recent retrospective review at the authors' institution also supports improved outcomes with modern systemic chemotherapy and targeted therapies, particularly in patients diagnosed with LM at metastatic presentation and who are typically naïve to systemic treatment.³⁰ Patients with NSCLC are living longer, and CNS progression is often seen in patients with EGFR+ and ALK+ tumors after progression on targeted therapy, which is difficult to treat. Whether this is a feature of the disease itself or the consequence of better systemic therapies and longer life is unclear.

Many patients with LM have severe neurologic complications and poor functional status. Default category 2A NCCN recommendations for patients with ALK+ NSCLC and poor functional status (ECOG performance status of 3–4) after crizotinib and other first-line chemotherapy treatments include best supportive care. Effective pain control and integrated palliative care are always critical in patients with LM whose disease has progressed despite multiple lines of therapy. The hope is that more effective targeted therapies, including ALK inhibitors with increased CNS activity, will be more successful in treating this devastating complication of NSCLC.