Summary Background ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively ...identified to have an ALK fusion within the first-in-man phase 1 crizotinib study. Methods In this phase 1 study, patients with ALK -positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumour responses, duration of response, time to tumour response, progression-free survival (PFS), overall survival at 6 and 12 months, and determination of the safety and tolerability and characterisation of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analysed in evaluable patients and PFS and safety were analysed in all patients. This study is registered with ClinicalTrials.gov , number NCT00585195. Findings Between Aug 27, 2008, and June 1, 2011, 149 ALK -positive patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60·8%, 95% CI 52·3–68·9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7·9 weeks (range 2·1–39·6) and median duration of response was 49·1 weeks (95% CI 39·3–75·4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9·7 months (95% CI 7·7–12·8). Median overall survival data are not yet mature, but estimated overall survival at 6 and 12 months was 87·9% (95% CI 81·3–92·3) and 74·8% (66·4–81·5), respectively. 39 patients continued to receive crizotinib for more than 2 weeks after progression because of perceived ongoing clinical benefit from the drug (12 for at least 6 months from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral oedema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphataemia (n=6), and lymphopenia (n=6). Interpretation Crizotinib is well tolerated with rapid, durable responses in patients with ALK -positive NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed. Funding Pfizer.
Summary Background Anaplastic lymphoma kinase ( ALK ) gene rearrangements are oncogenic drivers of non-small-cell lung cancer (NSCLC). Brigatinib (AP26113) is an investigational ALK inhibitor with ...potent preclinical activity against ALK mutants resistant to crizotinib and other ALK inhibitors. We aimed to assess brigatinib in patients with advanced malignancies, particularly ALK -rearranged NSCLC. Methods In this ongoing, single-arm, open-label, phase 1/2 trial, we recruited patients from nine academic hospitals or cancer centres in the USA and Spain. Eligible patients were at least 18 years of age and had advanced malignancies, including ALK -rearranged NSCLC, and disease that was refractory to available therapies or for which no curative treatments existed. In the initial dose-escalation phase 1 stage of the trial, patients received oral brigatinib at total daily doses of 30–300 mg (according to a standard 3 + 3 design). The phase 1 primary endpoint was establishment of the recommended phase 2 dose. In the phase 2 expansion stage, we assessed three oral once-daily regimens: 90 mg, 180 mg, and 180 mg with a 7 day lead-in at 90 mg; one patient received 90 mg twice daily. We enrolled patients in phase 2 into five cohorts: ALK inhibitor-naive ALK -rearranged NSCLC (cohort 1), crizotinib-treated ALK -rearranged NSCLC (cohort 2), EGFRT790M -positive NSCLC and resistance to one previous EGFR tyrosine kinase inhibitor (cohort 3), other cancers with abnormalities in brigatinib targets (cohort 4), and crizotinib-naive or crizotinib-treated ALK -rearranged NSCLC with active, measurable, intracranial CNS metastases (cohort 5). The phase 2 primary endpoint was the proportion of patients with an objective response. Safety and activity of brigatinib were analysed in all patients in both phases of the trial who had received at least one dose of treatment. This trial is registered with ClinicalTrials.gov , number NCT01449461. Findings Between Sept 20, 2011, and July 8, 2014, we enrolled 137 patients (79 58% with ALK -rearranged NSCLC), all of whom were treated. Dose-limiting toxicities observed during dose escalation included grade 3 increased alanine aminotransferase (240 mg daily) and grade 4 dyspnoea (300 mg daily). We initially chose a dose of 180 mg once daily as the recommended phase 2 dose; however, we also assessed two additional regimens (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg) in the phase 2 stage. four (100% 95% CI 40–100) of four patients in cohort 1 had an objective response, 31 (74% 58–86) of 42 did in cohort 2, none (of one) did in cohort 3, three (17% 4–41) of 18 did in cohort 4, and five (83% 36–100) of six did in cohort 5. 51 (72% 60–82) of 71 patients with ALK -rearranged NSCLC with previous crizotinib treatment had an objective response (44 62% (50–73) had a confirmed objective response). All eight crizotinib-naive patients with ALK -rearranged NSCLC had a confirmed objective response (100% 63–100). Three (50% 95% CI 12–88) of six patients in cohort 5 had an intracranial response. The most common grade 3–4 treatment-emergent adverse events across all doses were increased lipase concentration (12 9% of 137), dyspnoea (eight 6%), and hypertension (seven 5%). Serious treatment-emergent adverse events (excluding neoplasm progression) reported in at least 5% of all patients were dyspnoea (ten 7%), pneumonia (nine 7%), and hypoxia (seven 5%). 16 (12%) patients died during treatment or within 31 days of the last dose of brigatinib, including eight patients who died from neoplasm progression. Interpretation Brigatinib shows promising clinical activity and has an acceptable safety profile in patients with crizotinib-treated and crizotinib-naive ALK -rearranged NSCLC. These results support its further development as a potential new treatment option for patients with advanced ALK -rearranged NSCLC. A randomised phase 2 trial in patients with crizotinib-resistant ALK -rearranged NSCLC is prospectively assessing the safety and efficacy of two regimens assessed in the phase 2 portion of this trial (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg). Funding ARIAD Pharmaceuticals.
Summary Background No targeted therapies are available for KRAS -mutant non-small-cell lung cancer (NSCLC). Selumetinib is an inhibitor of MEK1/MEK2, downstream of KRAS, with preclinical evidence of ...synergistic activity with docetaxel in KRAS -mutant cancers. We did a prospective, randomised, phase 2 trial to assess selumetinib plus docetaxel in previously treated patients with advanced KRAS -mutant NSCLC. Methods Eligible patients were older than 18 years of age; had histologically or cytologically confirmed stage IIIB–IV KRAS -mutant NSCLC; had failed first-line therapy for advanced NSCLC; had WHO performance status of 0–1; had not received previous therapy with either a MEK inhibitor or docetaxel; and had adequate bone marrow, renal, and liver function. Patients were randomly assigned (in a 1:1 ratio) to either oral selumetinib (75 mg twice daily in a 21 day cycle) or placebo; all patients received intravenous docetaxel (75 mg/m2 on day 1 of a 21 day cycle). Randomisation was done with an interactive voice response system and investigators, patients, data analysts, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival, analysed for all patients with confirmed KRAS mutations. This study is registered with ClinicalTrials.gov , number NCT00890825. Findings Between April 20, 2009, and June 30, 2010, we randomly assigned 44 patients to receive selumetinib and docetaxel (selumetinib group) and 43 to receive placebo and docetaxel (placebo group). Of these, one patient in the selumetinib group and three in the placebo group were excluded from efficacy analyses because their tumours were not confirmed to be KRAS -mutation positive. Median overall survival was 9·4 months (6·8–13·6) in the selumetinib group and 5·2 months (95% CI 3·8–non-calculable) in the placebo group (hazard ratio HR for death 0·80, 80% CI 0·56–1·14; one-sided p=0·21). Median progression-free survival was 5·3 months (4·6–6·4) in the selumetinib group and 2·1 months (95% CI 1·4–3·7) in the placebo group (HR for progression 0·58, 80% CI 0·42–0·79; one-sided p=0·014). 16 (37%) patients in the selumetinib group and none in the placebo group had an objective response (p<0·0001). Adverse events of grade 3 or higher occurred in 36 (82%) patients in the selumetinib group and 28 (67%) patients in the placebo group. The most common grade 3–4 adverse events were neutropenia (29 67% of 43 patients in the selumetinib group vs 23 55% of 42 patients in the placebo group), febrile neutropenia (eight 18% of 44 patients in the selumetinib group vs none in the placebo group), dyspnoea (one 2% of 44 patients in the selumetinib group vs five 12% of 42 in the placebo group), and asthenia (four 9% of 44 patients in the selumetinib group vs none in the placebo group). Interpretation Selumetinib plus docetaxel has promising efficacy, albeit with a higher number of adverse events than with docetaxel alone, in previously treated advanced KRAS -mutant NSCLC. These findings warrant further clinical investigation of selumetinib plus docetaxel in KRAS -mutant NSCLC. Funding AstraZeneca.
The central nervous system (CNS) is a common site of progression among patients with ROS1-rearranged lung cancer receiving crizotinib. We conducted a phase 2 study to evaluate the intracranial ...efficacy of lorlatinib in patients with ROS1-rearranged lung cancer who developed CNS-only progression on crizotinib.
Patients with metastatic ROS1-rearranged lung cancer with CNS-only progression on crizotinib received lorlatinib 100 mg daily. The primary end point was intracranial disease control rate at 12 weeks per modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included intracranial and extracranial progression-free survival, intracranial objective response rate, and safety/tolerability.
A total of 16 patients were enrolled between November 2016 and January 2019. Nine patients (56%) had received prior CNS radiation, with a median of 10.9 months between radiation and lorlatinib. At 12 weeks, the intracranial disease control rate was 100% and intracranial objective response rate was 87%. While on study, the complete intracranial response was 60%. With median follow-up of 22 months, seven patients experienced disease progression, including five patients with CNS relapse. The median intracranial and extracranial progression-free survivals were 38.8 months (95% confidence interval: 16.9–not reported) and 41.1 months (95% confidence interval: 17.6–not reported), respectively. Molecular analysis of plasma or tissue from patients with extracranial progression on lorlatinib revealed ROS1 G2032R (n = 1), ROS1 L2086F (n = 1), and CCDC6-RET fusion plus ROS1 G2032R (n = 1). The safety profile of lorlatinib was consistent with prior studies. There were 11 patients (69%) who required dose reduction, including one patient who discontinued treatment for grade 3 edema. No grade greater than or equal to 4 adverse events were observed.
Lorlatinib induced durable intracranial responses in patients with ROS1-rearranged NSCLC and prior isolated CNS progression on crizotinib.
Taletrectinib (AB-106/DS-6051b) is an oral, potent selective ROS1 and pan-NTRK tyrosine kinase inhibitor (TKI). Preclinically, taletrectinib has activity against ROS1 G2032R solvent-front mutation.
...Patients with ROS1+ NSCLC enrolled into two phase 1 studies conducted in United States (U101, NCT02279433) and Japan (J102, NCT02675491) were analyzed for objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors version 1.1, progression-free survival, and safety.
A total of 22 patients with ROS1+ NSCLC out of the total 61 patients enrolled were analyzed. Taletrectinib was given at the oral dose of 400 mg, 600 mg, 800 mg, and 1200 mg once daily and 400 mg twice daily as part of the dose-escalation schema. Data cutoff was August 19, 2020. Median follow-up time for all 22 patients was 14.9 months (95% confidence interval CI: 4.1–33.8). A total of 18 patients with ROS1+ were assessable for response. The confirmed ORR for ROS1 TKI-naive patients (N = 9) was 66.7% (95% CI: 35.4–87.9) with a disease control rate of 100% (70.1–100). The confirmed ORR for crizotinib pretreated patients (N = 6) was 33.3% (95% CI: 9.7–70.0) with a disease control rate of 88.3% (95% CI: 443.6–97.0). The median progression-free survival for ROS1 TKI-naive patients (N = 11) was 29.1 months (95% CI: 2.6–not reached) and 14.2 months (95% CI: 1.5–not reached) for crizotinib-refractory only patients (N = 8). The most common treatment-related adverse events were alanine transaminase elevations (72.7%), aspartate transaminase elevations (72.7%), nausea (50.0%), and diarrhea (50.0%). Grade 3 or higher adverse events were alanine transaminase elevations (18.2%), aspartate transaminase (9.1%), and diarrhea (4.5%).
Taletrectinib (AB106/DS6051b) has a meaningful clinical activity in patients with advanced ROS1+ NSCLC who are ROS1 TKI-naive or crizotinib-refractory and a manageable safety profile.
RET rearrangements define a distinct molecular subset of NSCLC. The multikinase inhibitor ponatinib reveals potent activity in preclinical models of RET-rearranged NSCLC.
In this single-arm, ...multicenter, phase II trial, we evaluated the clinical activity of ponatinib in patients with advanced, previously treated, RET-rearranged NSCLC (NCT01813734). RET rearrangements were identified through fluorescence in situ hybridization or next-generation sequencing. Ponatinib was administered at a dose of 30 mg once daily. Patients without a documented objective response were eligible to dose-escalate ponatinib to 45 mg daily. The primary end point was objective response rate.
Between August 2014 and December 2017, nine patients were enrolled. The median age was 58 years (range 49–73 y). Eight patients (89%) had a history of brain metastases. The median number of previous lines of therapy was three (range 1–5). Of the nine evaluated patients, five (55%) experienced tumor shrinkage from baseline, but no confirmed responses were observed (objective response rate 0%). The disease control rate was 55%. With a median follow-up of 9.33 months, the median progression-free survival and overall survival were 3.80 months (95% CI: 1.83–5.30) and 17.47 months (95% CI: 6.57–19.20), respectively. The most common treatment-related adverse events were rash (n = 5; 56%), constipation (n = 4; 44%), and diarrhea (n = 4; 44%). No treatment-related thromboembolic or cardiac events were observed. The study was stopped prematurely owing to slow accrual and lack of clinical activity.
Ponatinib has limited clinical activity in patients with RET-rearranged NSCLC. Continued development of more potent and selective RET inhibitors is needed.
...clinical data standards strive to define and standardize data relevant to clinical topics in cardiology, with the primary goal of assisting data collection by providing a platform of data elements ...and definitions applicable to various conditions. The increasing national focus on adoption of certified EHRs along with financial incentives for providers to demonstrate "meaningful use" of those EHRs to improve healthcare quality render even more imperative and urgent the need for such definitions and standards. ...the ACCF and AHA have undertaken to define and disseminate clinical data standards--sets of standardized data elements and corresponding definitions--to collect data relevant to cardiovascular conditions.
Summary Background Alectinib—a highly selective, CNS-active, ALK inhibitor—showed promising clinical activity in crizotinib-naive and crizotinib-resistant patients with ALK -rearranged ( ALK ...-positive) non-small-cell lung cancer (NSCLC). We aimed to assess the safety and efficacy of alectinib in patients with ALK -positive NSCLC who progressed on previous crizotinib. Methods We did a phase 2 study at 27 centres in the USA and Canada. We enrolled patients aged 18 years or older with stage IIIB–IV, ALK -positive NSCLC who had progressed after crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death, or withdrawal. The primary endpoint was the proportion of patients achieving an objective response by an independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the response-evaluable population (ie, patients with measurable disease at baseline who received at least one dose of study drug), and efficacy and safety analyses were done in the intention-to-treat population (all enrolled patients). This study is registered with ClinicalTrials.gov , number NCT01871805 . The study is ongoing and patients are still receiving treatment. Findings Between Sept 4, 2013, and Aug 4, 2014, 87 patients were enrolled into the study (intention-to-treat population). At the time of the primary analysis (median follow-up 4·8 months IQR 3·3–7·1), 33 of 69 patients with measurable disease at baseline had a confirmed partial response; thus, the proportion of patients achieving an objective response by the independent review committee was 48% (95% CI 36–60). Adverse events were predominantly grade 1 or 2, most commonly constipation (31 36%), fatigue (29 33%), myalgia 21 24%), and peripheral oedema 20 23%). The most common grade 3 and 4 adverse events were changes in laboratory values, including increased blood creatine phosphokinase (seven 8%), increased alanine aminotransferase (five 6%), and increased aspartate aminotransferase (four 5%). Two patients died: one had a haemorrhage (judged related to study treatment), and one had disease progression and a history of stroke (judged unrelated to treatment). Interpretation Alectinib showed clinical activity and was well tolerated in patients with ALK -positive NSCLC who had progressed on crizotinib. Therefore, alectinib could be a suitable treatment for patients with ALK -positive disease who have progressed on crizotinib. Funding F Hoffmann-La Roche.
Summary Background Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor, which has shown robust anti-tumour efficacy, along with intracranial activity, in patients with ALK ...-rearranged non-small-cell lung cancer. In phase 1 and 2 studies, ceritinib has been shown to be highly active in both ALK inhibitor-naive and ALK inhibitor-pretreated patients who had progressed after chemotherapy (mostly multiple lines). In this study, we compared the efficacy and safety of ceritinib versus single-agent chemotherapy in patients with advanced ALK -rearranged non-small-cell lung cancer who had previously progressed following crizotinib and platinum-based doublet chemotherapy. Methods In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged at least 18 years with ALK -rearranged stage IIIB or IV non-small-cell lung cancer (with at least one measurable lesion) who had received previous chemotherapy (one or two lines, including a platinum doublet) and crizotinib and had subsequent disease progression, from 99 centres across 20 countries. Other inclusion criteria were a WHO performance status of 0–2, adequate organ function and laboratory test results, a life expectancy of at least 12 weeks, and having recovered from previous anticancer treatment-related toxicities. We randomly allocated patients (1:1; with blocking block size of four; stratified by WHO performance status 0 vs 1–2 and presence or absence of brain metastases) to oral ceritinib 750 mg per day fasted (in 21 day treatment cycles) or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 investigator choice, every 21 days). Patients who discontinued chemotherapy because of progressive disease could cross over to the ceritinib group. The primary endpoint was progression-free survival, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumors 1.1 in the intention-to-treat population, assessed every 6 weeks until month 18 and every 9 weeks thereafter. This trial is registered with ClinicalTrials.gov , number NCT01828112 , and is ongoing but no longer recruiting patients. Findings Between June 28, 2013, and Nov 2, 2015, we randomly allocated 231 patients; 115 (50%) to ceritinib and 116 (50%) to chemotherapy (40 34% to pemetrexed, 73 63% to docetaxel, and three 3% discontinued before receiving treatment). Median follow-up was 16·5 months (IQR 11·5–21·4). Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy (5·4 months 95% CI 4·1–6·9 for ceritinib vs 1·6 months 1·4–2·8 for chemotherapy; hazard ratio 0·49 0·36–0·67; p<0·0001). Serious adverse events were reported in 49 (43%) of 115 patients in the ceritinib group and 36 (32%) of 113 in the chemotherapy group. Treatment-related serious adverse events were similar between groups (13 11% in the ceritinib group vs 12 11% in the chemotherapy group). The most frequent grade 3–4 adverse events in the ceritinib group were increased alanine aminotransferase concentration (24 21% of 115 vs two 2% of 113 in the chemotherapy group), increased γ glutamyltransferase concentration (24 21% vs one 1%), and increased aspartate aminotransferase concentration (16 14% vs one 1% in the chemotherapy group). Six (5%) of 115 patients in the ceritinib group discontinued because of adverse events compared with eight (7%) of 116 in the chemotherapy group. 15 (13%) of 115 patients in the ceritinib group and five (4%) of 113 in the chemotherapy group died during the treatment period (from the day of the first dose of study treatment to 30 days after the final dose). 13 (87%) of the 15 patients who died in the ceritinib group died because of disease progression and two (13%) died because of an adverse event (one 7% cerebrovascular accident and one 7% respiratory failure); neither of these deaths were considered by the investigator to be treatment related. The five (4%) deaths in the chemotherapy group were all due to disease progression. Interpretation These findings show that patients derive significant clinical benefit from a more potent ALK inhibitor after failure of crizotinib, and establish ceritinib as a more efficacious treatment option compared with chemotherapy in this patient population. Funding Novartis Pharmaceuticals Corporation.
Summary Background ALK -rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK tyrosine kinase inhibitors (ALK inhibitors) such as crizotinib, but resistance invariably develops, often ...with progression in the brain. Ceritinib is a more potent ALK inhibitor than crizotinib in vitro, crosses the blood–brain barrier in vivo, and shows clinical responses in patients with crizotinib-resistant disease. We aimed to assess whole-body activity of ceritinib in both ALK inhibitor-pretreated and ALK inhibitor-naive patients with ALK -rearranged NSCLC. Methods ASCEND-1 was an open-label, phase 1 trial that recruited patients from 20 academic hospitals or cancer centres in 11 countries in Europe, North America, and Asia-Pacific. Eligible patients were aged 18 years or older with ALK -rearranged locally advanced or metastatic cancer that had progressed despite standard therapy (or for which no effective standard therapy existed), who had at least one measurable lesion at baseline. The primary objective (to determine the maximum tolerated dose) has been reported previously. This updated analysis includes all patients with ALK -rearranged NSCLC given oral ceritinib at the recommended dose of 750 mg/day in the dose-escalation and expansion phases. Here we report the secondary outcomes of overall response, duration of response, and progression-free survival, analysed in all patients who received at least one 750 mg dose of ceritinib. Exploratory analyses included retrospective analysis of intracranial activity by independent neuroradiologists, in patients with untreated or locally treated neurologically stable brain metastases at baseline. Safety was assessed in all patients who received at least one dose of ceritinib. This study is no longer recruiting patients; however, treatment and follow-up are ongoing. This study is registered with ClinicalTrials.gov , number NCT01283516. Findings Between Jan 24, 2011, and July 31, 2013, 255 patients were enrolled and received at least one dose of ceritinib 750 mg/day, of whom 246 had ALK -rearranged NSCLC. At data cutoff (April 14, 2014), median follow-up was 11·1 months (IQR 6·7–15·2) and 147 (60%) patients had discontinued treatment, 98 (40%) as a result of disease progression. An overall response was reported in 60 (72% 95% CI 61–82) of 83 ALK inhibitor-naive patients and 92 (56% 49–64) of 163 ALK inhibitor-pretreated patients. Median duration of response was 17·0 months (95% CI 11·3–non-estimable NE) in ALK inhibitor-naive patients and 8·3 months (6·8–9·7) in ALK inhibitor-pretreated patients. Median progression-free survival was 18·4 months (95% CI 11·1–NE) in ALK inhibitor-naive patients and 6·9 months (5·6–8·7) in ALK inhibitor-pretreated patients. Of 94 patients with retrospectively confirmed brain metastases and at least one post-baseline MRI or CT tumour assessment, intracranial disease control was reported in 15 (79% 95% CI 54–94) of 19 ALK inhibitor-naive patients and in 49 (65% 54–76) of 75 ALK inhibitor-pretreated patients. Of these 94 patients, 11 had measurable brain lesions and no previous radiotherapy to the brain, six of whom achieved a partial intracranial response. Serious adverse events were recorded in 117 (48%) of 246 patients. The most common grade 3–4 laboratory abnormalities were increased alanine aminotransferase (73 30% patients) and increased aspartate aminotransferase (25 10%). The most common grade 3–4 non-laboratory adverse events were diarrhoea and nausea, both of which occurred in 15 (6%) patients. Two on-treatment deaths during the study were deemed to be related to study drug by the investigators, one due to interstitial lung disease and one as a result of multiorgan failure that occurred in the context of infection and ischaemic hepatitis. Interpretation The durable whole-body responses reported, together with the intracranial activity, support a clinical benefit for treatment with ceritinib in patients with ALK -rearranged NSCLC who have received crizotinib, or as an alternative to crizotinib. A confirmatory phase 2 clinical trial is ongoing to assess ceritinib activity in patients with ALK -rearranged NSCLC and brain or leptomeningeal metastases. Funding Novartis Pharmaceuticals Corporation.
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