This study provides prospective evidence suggesting clinical benefit with a systemic regimen for HER2+ LM. We observed longer survival in patients with LM from HER2+ mBC who were treated with tucatinib, trastuzumab and capecitabine, relative to historical controls. We also observed an improvement in neurological signs and symptoms in most patients and objective LM responses in over a third of patients, using a composite criterion. Furthermore, the regimen was well tolerated. The safety data were consistent with data reported in previous studies of tucatinib in combination with trastuzumab and capecitabine9,11. These data expand the scope of the tucatinib triplet regimen in the CNS to LM from HER2+ BC.
Diagnosis and response assessment in LM is challenging, in part due to the poor sensitivity of CSF cytology, the poor specificity of imaging and neurological symptoms that can be difficult to interpret and attribute. Although most studies utilize a composite assessment of CSF cytopathology, neuroaxis imaging and neurological clinical evaluation, no validated algorithm for evaluation exists. In this study, response of LM to treatment was determined using an adaptation of the criteria proposed by the Response Assessment in Neuro-Oncology–Leptomeningeal Metastases (RANO-LM) working group14. According to these criteria, approximately one-third of patients achieved a composite response. In addition, our study is encouraging in that most patients achieved neurological clinical benefit from the regimen. Most experienced improvement of neurological deficits, which is not commonly reported with LM-directed drug therapies, for which the goal historically has been to delay further neurological deterioration.
In this study, tucatinib and ONT-993 were detectable in the CSF of all 13 patients for whom CSF data were available after the first tucatinib dose and were comparable to steady-state unbound plasma concentrations. This study documented evidence of tucatinib distribution in the CSF in patients with HER2+ mBC and supported the previously observed activity in patients with brain metastases. The tucatinib unbound plasma fractions in actual individual patients in this study were not estimated and may affect the estimation of the CSF-to-plasmaub ratios, although it is not anticipated to greatly impact the overall interpretations. Although detected in the CSF, ONT-993 is not expected to contribute to overall pharmacological activity based on the concentrations and potency. Circulating tumor (ct)DNA analysis with matched CSF and blood correlative samples is under way and will be reported separately.
The most appropriate endpoint for LM trials is the subject of ongoing discourse15. As response assessment in LM can be difficult to determine and prognosis in this patient population is often determined by LM, we chose OS as our primary endpoint. Nevertheless, identifying an appropriate historical control in LM is difficult. Until recently, the body of the LM literature comprised primarily retrospective studies in addition to six randomized studies16,17,18,19,20,21. These studies—most published one or more decades ago—tended to be small and include heterogeneous populations of patients, with variable endpoints and criteria for LM diagnosis and response assessment. In clinical practice, management of LM varies widely and is primarily guided by expert opinion.
Since the development of our study, a randomized study of intrathecal cytarabine in LM has been reported, as well as two prospective studies on intrathecal trastuzumab in the HER2+ LM population, a randomized study evaluating proton craniospinal radiation in LM and small retrospective studies of trastuzumab–deruxtecan, which included patients with LM20,22,23,24,25. Although these contemporary studies represent important advances, the literature still suffers from a heterogeneous patient population and a lack of harmonization of study criteria and endpoints, relative rarity, complicated clinical courses and the absence of validated response assessment criteria.
Oberkampf et al. reported in a phase 2 study of intrathecal trastuzumab that, among 19 patients with HER2+ BC LM, the median LM-related PFS was 5.9 months and the median OS was 7.9 months. The clinical neurological PFS after 8 weeks of treatment was the primary endpoint of the study: 14 patients (74%) were free of neurological progression at 8 weeks (ref. 22). In a phase 1 and 2 study, Kumthekar et al. reported a median overall survival of 10.5 months for the phase 2 dose-treated subset of 23 patients with HER2+ BC and a median PFS of 2.8 months (ref. 23). The primary endpoint of the study was disease response, utilizing a scale integrating clinical, radiographic and cytological response; the response rate was 17.9% for the HER2+ BC cohort23. Intrathecal trastuzumab was well tolerated in both studies. Our median OS is consistent with these two studies and all patients fared better than the median OS of 4–5 months reported in historical controls. Of further interest, in a randomized phase 2 study, Yang et al. found that proton craniospinal radiation was well tolerated and notably improved both CNS PFS (median 7.5 months versus 2.3 months; the primary endpoint) and OS (9. months versus 6 months) over photon involved-field radiation in patients with LM and nonsmall-cell lung cancer and BC26. In addition, a recent study provides the first randomized evidence of clinical benefit of intrathecal chemotherapy in LM. In the intent-to-treat group, median LM PFS (the primary endpoint) was 3.8 months in the experimental group (intrathecal cytarabine plus physician’s choice of systemic therapy) versus 2.2 months in the control group (systemic therapy alone) (P = 0.04); median OS was 7.3 months in the experimental group versus 4 months in the control group (P = 0.51)20. Their new agents are under investigation for the treatment of LM24,25,27. Recently, the antibody–drug conjugate trastuzumab–deruxtecan demonstrated activity in two small retrospective studies in patients with HER2+ LM. ROSET-BM (n = 19 with LM) showed 12-month PFS and OS rates of 60.7% and 87.1%, respectively25. In a case series of eight patients with HER2+ LM, all patients derived clinical benefit and four (50%) achieved a partial radiographic response24.
Our study provides an important addition to the contemporary literature about the management of LM beyond the favorable efficacy and safety data described above. The study only included patients with HER2+ mBC and newly diagnosed, untreated LM, as opposed to earlier trials which often included more heterogenous populations. Still, many of our patients had previously diagnosed parenchymal brain metastases treated with modalities to include radiation and therefore represent a recurrent CNS metastases population. Furthermore, the study entry criteria required CSF confirmation of LM or MRI evidence (MRI reviewed by a radiologist) plus neurological signs and/or symptoms attributed to LM, increasing the confidence that enrolled patients in fact had a diagnosis of LM. A particular strength of our study was the prospective evaluation of patient-reported outcomes. Notably, many patients experienced improvement in patient-reported QoL and symptom burden, with both the mean LASA and the mean MDASI-BT overall scores improved compared to baseline. Improvements in QoL have not been consistently reported with intrathecal chemotherapies and radiation therapy, including proton craniospinal Irradiation, may come with a cost to QoL and short-term and long-term cognition. Importantly, this study provides evidence of the feasibility of enrolling LM patients to a systemic therapy trial, even on the background of the COVID pandemic.
Important questions are now raised about sequencing available therapies in LM, particularly in patients with HER2+ mBC. The availability of a systemic regimen for treating LM may represent an opportunity to defer intrathecal therapy, which is a more invasive treatment administered often weekly or even twice weekly that may negatively impact QoL for patients. Furthermore, although intrathecal chemotherapy is most suitable for treating microscopic and linear macroscopic LM due to its limited penetrance beyond the subarachnoid space28, tucatinib in combination with trastuzumab and capecitabine affords an opportunity to treat nodular LM along with parenchymal brain metastasis and systemic disease. This regimen may also represent an opportunity to defer radiation to the neuroaxis, particularly in patients who are asymptomatic or minimally symptomatic.
The current study has several limitations. First, although actual accrual initially outpaced projected accrual rates, the study was terminated early due to lack of accrual after the FDA approval of tucatinib in combination with trastuzumab and capecitabine for patients with HER2+ mBC with and without brain metastasis. Second, given that LM from HER2+ mBC is a rare disease, and considering the limited LM literature, the study was designed as a single arm utilizing a historical control based on retrospective data. Historically, patients with LM largely had progressive systemic disease and poor functional status at the time of diagnosis. Today, many patients present with stable or controlled systemic disease and good or excellent functional status, mirroring our enrolled patients. As is typically the case in LM studies, CSF confirmation of LM was not a requirement for enrollment in our study. However, patients without positive CSF cytology did have neuroaxis imaging consistent with LM, as well as clinical findings (neurological signs and/or symptoms). Although our clinical trial conditions may not be entirely generalizable to the broader LM population, the study did allow enrollment of patients with a relatively low functional status and, given the tolerability and ease of use and convenient schedule compared to intrathecal therapy, it may be an option available to a broad population of patients with HER2+ LM.
The combination of tucatinib, capecitabine and trastuzumab achieved a clinically meaningful improvement in OS in relation to historical controls for patients with LM from HER2+ mBC, as well as improvement in neurological symptoms and signs in most participants. The combination was well tolerated with a manageable safety profile. This study provides the prospective data of a HER2+-directed systemic therapy providing clinically meaningful benefit for patients with LM from HER2+ BC. Although this is an importance advance, further studies evaluating CNS-penetrant drugs, as well as the best combinations and sequence of therapies in this patient population, are needed. Unanswered questions include whether there may be an additive or synergistic benefit of combining the tucatinib regimen with intrathecal therapies, such as intrathecal trastuzumab. Planned future analysis for this study include evaluating blood and CSF samples to assess circulating tumor (ct)DNA concentrations and genomic sequencing to identify candidate biomarkers that may predict response to therapy and provide better understanding of underlying mechanisms.
