Abstract
Background:
Human epidermal growth factor receptor 2 (HER2, ERBB2) mutations are found in approximately 2% of lung adenocarcinomas. The frequency and clinical course of brain metastases in this oncogenic subset are ill defined.
Methods:
Baseline and subsequent development of brain metastases was evaluated in consecutive patients with HER2-mutant (N = 98), EGFR-mutant (N = 200), and KRAS-mutant (N = 200) lung cancers.
Results:
At metastatic diagnosis, the odds ratio (OR) for brain metastases was similar in patients whose tumors harbored HER2-mutations (19%) compared to patients with KRAS-mutations (24%; HER2 vs. KRAS, OR 0.7, P = 0.33) and EGFR-mutations (31%; HER2 vs. EGFR, OR 0.5, P = 0.24). Lung cancer patients with HER2-mutations developed more brain metastases on treatment than patients with KRAS-mutations (28% vs. 8%, hazard ratio [HR] 5.2, P < .001), and trended more than patients with EGFR-mutations (28% vs 16%, HR 1.7, P = .06). Patients with HER2 YVMA mutations also developed more brain metastases on treatment than patients with KRAS-mutations (HR 5.9, P < .001). Median overall survival (OS) was shorter for patients with HER2-mutant (1.6 years; P < .001) or KRAS-mutant (1.1 years; P < .001) lung cancers compared to EGFR-mutant lung cancer patients (3.0 years). Brain metastases occurred in 47% of patients with HER2-mutant lung cancers, which imparted a shorter OS (HR 2.7, P < .001).
Conclusions:
These data provide a framework for brain imaging surveillance in patients with HER2-mutant lung cancers and underpins the need to develop HER2-targeted agents with central nervous system activity.
Keywords: Receptor, ErbB-2, Lung Neoplasms, Brain Metastasis, Oncogenes, Mutation
Precis:
Oncogenic driver mutations influence the disease course, treatment options, and the development of brain metastases in patients with lung cancers. Results from this retrospective analysis of 498 patients with HER2-, KRAS- or EGFR-mutant lung cancers finds that HER2-driven lung cancers have reduced overall survival and were at increased risk of developing brain metastases while on treatment.
Introduction
Oncogenic mutations in human epidermal growth factor receptor 2 (HER2, also known as ERBB2) occur in 2% of lung adenocarcinomas.1–3 Partially due to an absence of effective, targeted therapies, HER2 mutations are associated with worse outcomes compared to other oncogenic drivers.4–6 The standard of care for the treatment of HER2-mutant lung cancers remains cytotoxic chemotherapy.7–9
Brain metastases are common in the natural history of lung cancers and will arise in 20–50% of patients with metastatic non-small cell lung cancers (NSCLC).10,11 The development of brain metastases is associated with decreased quality of life and only a 4–6 month median survival in NSCLC.12 In contrast to HER2-amplified breast cancers that are well characterized, less is known about the propensity of HER2-mutant lung cancers to develop brain metastases. Because HER2-amplified breast cancers are more likely to develop brain metastases through constitutive HER2 signaling, we hypothesize that HER2-mutant lung cancers are also more apt to develop brain metastases compared to lung cancers driven by other oncogenes.13–15
This study aims to characterize the association between brain metastases and HER2-mutant lung cancers, including examination of a 12 base pair, in-frame insertion (p.A775 G776insYVMA) in exon 20 (HER2 YVMA). HER2 YVMA is the most frequently occurring HER2 mutation in lung cancers.1,2,5 The oncogenic activity of the HER2 YVMA mutation is well described and occurs through downstream activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways.16,17
For context with other NSCLC patients, rates of brain metastasis in HER2-mutant lung cancers were compared to frequencies in the more readily studied EGFR- and KRAS-mutant lung adenocarcinomas. KRAS-mutant lung cancers comprise 29–33% of lung adenocarcinomas, and 17–55% of these patients develop brain metastases.18–20 EGFR-mutant lung cancers comprise 11–25% of lung adenocarcinomas,20,21 with up to 60% of these patients developing brain metastases or leptomeningeal disease during their illness.18,22–24 Unlike the molecularly defined subset of lung cancers harboring an EGFR mutation,25 HER2- and KRAS-mutant lung cancers do not currently have FDA approved effective targeted therapies available.
The association between HER2 mutations and brain metastasis is important to quantify as it can both describe the clinical course of the disease and help to guide treatment. Information on brain metastases in this patient population is critical for the development of new agents targeting HER2 in lung cancers and for defining brain surveillance paradigms.
Methods
Design
We reviewed the records of 98 consecutive patients with metastatic HER2-mutant lung cancers seen at Memorial Sloan Kettering Cancer Center (MSK) from January 2007 through January 2017. A comparison cohort of patients identified using cBioPortal26,27 seen from February 2014 through January 2017, was comprised of 200 consecutive patients with metastatic KRAS-mutant and 200 consecutive patients with metastatic sensitizing EGFR-mutant (defined as EGFR L858R or exon 19 deletions) lung cancers. Mutations were identified via mutational hotspot testing by a mass spectrometry-based nucleic acid assay on the Sequenom platform (EGFR, HER2, KRAS, NRAS, BRAF, MAP2K1, PIK3CA, and AKT1) or broad hybrid capture next-generation sequencing (NGS) via MSK-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), or by other CLIA certified NGS platforms.28,29 Patients with co-occurring mutations in the 3 oncogenes of interest (HER2, EGFR, or KRAS) were excluded (N = 3). This study was approved by the MSK institutional review board and was conducted in accordance with the United States Common Rule.
All patients had pathologically confirmed stage IV (AJCC version 8 defined) or recurrent metastatic NSCLC. Patient clinicopathologic characteristics including age and mutation status were evaluated for association with the baseline presence and subsequent development of brain metastases. All patients underwent CNS imaging with either magnetic resonance or computed tomography at initial metastatic diagnosis. Subsequent brain imaging took place as per standard-of-care based on clinical assessment and/or symptoms suggestive of CNS progression.
Statistics and data analysis
Chi-square testing compared the demographic characteristics amongst the 3 cohorts. Baseline brain metastatic rates (odds ratios; ORs) among mutational subgroups were evaluated using a multivariate logistical regression model with adjustments for smoking status, age at diagnosis, and sex. Cox proportional hazards models were used to analyze overall survival (OS) and incidence of brain metastatic disease during treatment; the entry time for each subject was defined as the time of the mutational report to account for left truncation. For the incidence of developing brain metastatic disease on treatment, time-dependent weights were used to account for competing risk due to death.30 When brain metastatic disease, targeted therapy, or radiation treatment were used as covariates in Cox proportional hazards models, they were treated as time-varying. Kaplan-Meier Curves were compared using the log-rank test. The effect of targeted therapies on the development of brain metastatic disease was evaluated using the Fisher’s exact test.31 The median time from brain metastatic diagnosis to the time of radiation was evaluated using a one-way ANOVA. Data were analyzed in R with the crprep function in the mstate package used to compute time-dependent weights.32
Results
Demographics and HER2 profiles
We identified 98 patients with HER2-mutations, 200 with KRAS-mutations, and 200 patients with EGFR-mutations. Patients with EGFR- or HER2-mutant lung cancers were more likely to be < 65 years old at presentation than patients with KRAS-mutant lung cancers (P < .001 for both mutations; Table 1, Supporting Table 1). There was no significant difference in the distribution of sex amongst the groups (P = .52). Patients with KRAS-mutant lung cancers were more likely to have a history of smoking than patients with either HER2-mutant (P < .001) or EGFR-mutant lung cancers (P < .001; Table 1).
Table 1:
Demographics, treatment, and brain metastasis by oncogenic driver in patients with stage IV lung cancers or recurrent metastatic disease.
| Demographics and disease course | Total (N = 498) | HER2-mutant (N = 98) | KRAS-mutant (N = 200) | EGFR-mutant (N = 200) |
|---|---|---|---|---|
| Median age, No. (range) | 65 (24–90) | 63 (34–85) | 67 (35–90) | 63 (24–89) |
| Age < 65 years old, No. (%) | 257 (52%) | 58 (59%) | 78 (39%) | 121 (61%) |
| Sex | ||||
| Female, No. (%) | 317 (64%) | 62 (63%) | 122 (61%) | 133 (67%) |
| Male, No. (%) | 181 (36%) | 36 (37%) | 78 (39%) | 67 (34%) |
| Smoking Status | ||||
| Never, No. (%) | 182 (37%) | 52 (53%) | 13 (7%) | 117 (59%) |
| Ever, No. (median pack years) | 316 (25) | 46 (12) | 187 (34) | 83 (10) |
| Targeted Therapy | ||||
| Ever, No. (%) | 235 (47%) | 42 (43%) | 0 (0%) | 193 (97%) |
| Never, No. (%) | 263 (53%) | 56 (57%) | 200 (100%) | 7 (4%) |
| Brain Metastatic Disease | ||||
| Never, No. (%) | 294 (59%) | 52 (53%) | 136 (68%) | 106 (53%) |
| Ever, No. (%) | 204 (41%) | 46 (47%) | 64 (32%) | 94 (47%) |
| At Diagnosis, No. (%) | 129 (26%) | 19 (19%) | 48 (24%) | 62 (31%) |
| On Treatment, No. (%) | 75 (15%) | 27 (28%) | 16 (8%) | 32 (16%) |
| Local Cranial Therapy, No. (% of those with brain metastatic disease)† | 113 (55%) | 25 (54%) | 38 (59%) | 50 (53%) |
Cranial radiotherapy or metastasectomy
There were 27 unique HER2 mutations identified, including 14 known to be activating. Most patients with HER2-mutant lung cancer (N = 72) harbored an exon 20 insertion (Supporting Table 2). In total, 85 patients had a known, targetable mutation. An additional 13 unique HER2 alterations were classified as variants of unknown significance. Of the 98 patients in the HER2 cohort, 32 mutations were discovered using the Sequenom platform and the remaining 66 were found with targeted NGS.
Baseline brain metastasis
The frequency of brain metastases at diagnosis are shown in Table 1 and Figure 1. The incidence of baseline brain metastases was similar for both sexes (female versus male odds ratio [OR] 1.0, P = .94), but more common in younger (< 65 years old) patients (OR 1.8, P = .009). In the 19 patients with HER2-mutant lung cancers and brain metastasis at baseline diagnosis, 8 had a single brain metastasis, 11 had multiple brain metastases, and none had leptomeningeal disease by neuroimaging. The OR for baseline brain metastases was lower in the HER2-mutant cohort compared to the EGFR-mutant cohort, but similar for all other cohort comparisons including the HER2 YVMA subgroup (Table 2).
Figure 1.
Frequency of brain metastases at diagnosis and developing on treatment in patients with HER2-mutant, KRAS-mutant, and EGFR-mutant lung cancers.
Table 2:
The upper portion of the table depicts the odds ratios for the baseline presence of brain metastasis at diagnosis. The lower portion of the table delineates sub-distribution hazard ratios for the subsequent development of brain metastasis on treatment. Cohorts are grouped by driver mutation. Bold denotes comparisons with statistically significant differences.
| Baseline at time of diagnosis | Odds ratio | P-value |
|---|---|---|
| HER2 vs. KRAS | 0.7 | .33 |
| HER2 vs. EGFR | 0.5 | .03 |
| EGFR vs. KRAS | 1.4 | .24 |
| HER2 YVMA vs. EGFR | 0.5 | .09 |
| HER2 YVMA vs. KRAS | 0.6 | .28 |
| HER2 YVMA vs. HER2 non-YVMA | 1.0 | .99 |
| Subsequent development on treatment | Hazard ratio | P-value |
| HER2 vs. KRAS | 5.2 | <.001 |
| HER2 vs. EGFR | 1.7 | .06 |
| EGFR vs. KRAS | 3.0 | .001 |
| HER2 YVMA vs. EGFR | 1.8 | .14 |
| HER2 YVMA vs. KRAS | 5.9 | <.001 |
| HER2 YVMA vs. HER2 non-YVMA | 0.9 | .60 |
Development of brain metastasis on treatment
Among the 369 patients who did not have brain metastases at initial diagnosis, the cumulative incidence rate for development of brain metastases on treatment was higher for the HER2-mutant cohort compared to the KRAS-mutant cohort, and marginally higher relative to the EGFR-mutant cohort (Table 2, Fig. 2). Analysis of HER2-mutant subgroups indicated that patients with the HER2 YVMA mutation were significantly more likely to develop brain metastases on treatment than patients in the KRAS-cohort, but not the EGFR-cohort or patients with HER2 non-YVMA mutations (Table 2, Supporting Fig. S1A).
Figure 2.
The cumulative incidence rate of brain metastatic disease from the time of metastatic diagnosis amongst HER2-, EGFR-, and KRAS-mutant lung cancers. Analysis was carried out using a Cox proportional hazards model accounting for left-truncation and competing risk from death. Of note, there were 8 HER2- and 2 KRAS-mutant lung cancer patients who developed brain metastasis on treatment before their mutations were identified; since patients are considered at risk for developing brain metastasis after their mutation report date per the left truncation model, these 10 patients were excluded from the survival analysis.
Survival impact of brain metastasis
In total, 47% of patients with HER2-mutant or EGFR-mutant lung cancer experienced brain metastases compared to only 32% of patients with KRAS-mutant lung cancer (Fig. 1). Survival for patients with HER2-mutant lung cancers that ever-had brain metastases was reduced compared to those who never had brain metastases (Fig. 3, Supporting Fig. S2). In the HER2 YVMA mutant subgroup, those that ever-had brain metastatic disease had worse OS compared to those without brain metastatic disease (HR 2.8, 95% CI 1.3–6.3, P = .01).
Figure 3.
Overall survival (OS) is reduced in patients with brain metastases during disease course. (A) In the HER2-mutant cohort, the 52 patients without brain metastases had a median OS of 2.5 years (95% CI 1.4–not reached) versus the 46 patients with brain metastases who had a median OS of 1.2 years (95% CI 0.9–1.9 years). Patients with HER2-mutant lung cancers had shorter OS if they had brain metastases during their disease course (hazard ratio [HR] 2.7, 95% CI 1.5–4.8, Log-rank P < .001). (B) OS for all patients who ever had brain metastases (1.6 years) was decreased compared to patients without brain metastases (3.0 years). Patients with brain metastasis had reduced OS compared to patients without brain metastasis (HR 2.1; 95% CI 1.7–2.7, P < .001). Analyses were carried out and left truncation accounted for using a Cox proportional hazards model.
Survival impact of oncogenic drivers
OS was worse in patients with KRAS-mutant (OS 1.1 years, 95% CI 0.8–1.3 years; HR 2.0, 95% CI 1.5–2.7, P < .001) or HER2-mutant lung cancers (OS 1.6 years, 95% CI 1.3–2.2 years; HR 1.8, 95% CI 1.2–2.5, P = .002) compared to EGFR-mutant disease (OS 3.0 years, 95% CI 2.5–4.0 years). There was no difference in OS between KRAS- and HER2-mutant cohorts (HR 1.0, 95% CI 0.7–1.4, P = .98; Fig. 4). Patients with the HER2 YVMA mutation had similar survival (OS 1.3 years, 95% CI 1.2–2.4 years) to patients with KRAS mutations (HR 1.0, 95% CI 0.6–1.5, P = .89), but inferior survival compared to patients with EGFR mutations (HR 1.9, 95% CI 1.2–2.9, P = .005). There was no difference in OS between patients with the HER2 YVMA mutation or HER2 non-YVMA mutations (HER2 non-YVMA mutation OS 1.9 years, 95% CI 1.4–2.6 years; HR 1.1, 95% CI 0.7–2.0, P = .70; Supporting Fig. S1B).
Figure 4.
Overall survival (OS) for all patients by oncogenic driver. A Cox proportional hazards model, which accounted for left truncation, calculated OS as follows: HER2-mutant 1.6 years (95% CI 1.3–2.2 years), KRAS-mutant 1.1 years (95% CI 0.8–1.3 years), and EGFR-mutant 3.0 years (95% CI 2.5 – 4.0 years). The OS of the entire cohort of 498 patients was 2.0 years (95% CI 1.8–2.3).
Effects of HER2-targeted therapy
Forty-three percent (42/98) of patients in the HER2-mutant cohort received HER2-targeted therapy (afatinib, neratinib, ado-trastuzumab emtansine, trastuzumab, and/or dacomitinib; median time on treatment was 3.9 months (range 0.7–42.6 months)). Ninety-seven percent (193/200) of the EGFR-mutant cohort received targeted treatment (erlotinib, gefitinib, afatinib, and/or osimertinib). Of the 79 patients with HER2-mutant lung cancers but no baseline brain metastases, 44% (35/79) received HER2-targeted therapy. Forty-four percent (23/52) of patients in the HER2-mutant cohort who never developed brain metastases during the study received targeted treatment, and 44% (12/27) of the HER2-mutant cohort that developed brain metastases received HER2-targeted therapy. The use of HER2-targeted agents had no effect on the development of brain metastases (HR 1.2, P = .80) or survival (HR 1.3, P = .38).
Effects of brain radiotherapy
Fifty four percent (25/46) of patients with HER2 mutations and brain metastases received brain radiotherapy compared to 59% (38/64) of patients with KRAS- and 53% (50/94) of patients with EGFR-mutations. Median time from brain metastatic diagnosis to radiation was 29 days (range 1 day–5.1 years) in HER2-mutant, 29 days (range 0 days–2.4 years) in KRAS-mutant, and 31 days (range 0 days–3.9 years) in EGFR-mutant cohorts (P = .28). The median OS in patients with HER2-mutant lung cancers who received brain radiotherapy compared to those who did not was 1.1 vs. 1.5 years respectively (HR 2.5, 95% CI 1.3–4.6, P = .004).
Discussion
This study illustrates that patients with HER2-mutant lung cancers are significantly more likely to develop brain metastases while on treatment relative to patients with KRAS-mutant lung cancers and trended numerically more so than EGFR-mutant lung cancers. The propensity to develop brain metastases on treatment may be even more pronounced in the subgroup of patients who harbor the HER2 YVMA mutation.
The demographics and outcomes of patients in our study are in line with previously reported studies of HER2-mutant lung cancers.3,4,33,34 Consistent with previously published literature, our data show that patients with brain metastases were younger at diagnosis than patients without brain metastases, regardless of driver mutation.35 We found that the likelihood of having brain metastases at baseline diagnosis in patients with HER2-mutant lung cancers was comparable to the frequency in patients with KRAS-mutant lung cancers and trended toward being lower than the incidence in patients with EGFR-mutant lung cancers. This coincides with previously published data that EGFR-mutant lung cancers have a high incidence of brain metastasis at initial metastatic diagnosis.20,36
Despite a lower incidence of baseline brain metastasis, patients with HER2-mutant lung cancers had a higher risk of developing brain metastases on treatment compared to patients with KRAS-mutant lung cancers and trended toward increased incidence of brain metastasis on treatment as compared to EGFR-mutant lung cancers. Additionally, patients with EGFR-mutations without baseline brain metastases were more likely to develop brain metastatic disease compared to patients with KRAS-mutations. Patients with the HER2 YVMA mutation were significantly more likely to develop brain metastases on treatment compared to patients with KRAS-mutant lung cancers. In combination with studies demonstrating the activating and transforming nature of the HER2 YVMA mutation, the high rate of brain metastasis in patients with HER2-mutant lung cancers supports our hypothesis that HER2 oncogene activation is associated with an increased propensity for brain metastasis and is consistent with results found in the HER2-amplified breast cancer setting.13–15,37
There are several potential explanations for the high rate of brain metastasis in HER2-mutant lung cancers. For one, HER2-mutant cancers are associated with increased expression of the chemokine receptor C-X-C chemokine receptor type 4 (CXCR4). CXCR4 and its ligand, stromal-derived-factor-1 (SDF-1; also called CXCL12), may drive metastatic trafficking to the brain, though further studies are warranted.38,39 Secondly, poor systemic control with current treatments in patients with HER2-mutant lung cancers could also explain the difference in disease pattern relative to EGFR-mutant lung cancers. Targeted therapy did not decrease the incidence of brain metastases among patients with HER2-mutant lung cancers compared to chemotherapy. This negligible efficacy of HER2-targeted therapy on the incidence of brain metastasis is in line with the work of Eng et al., who found that chemotherapies showed larger improvements in OS than existing HER2-targeted therapies in patients with HER2-mutant lung cancers.6 The use of effective, targeted agents in patients with EGFR-mutant lung cancers may decrease the likelihood of metastatic trafficking to the brain. Heon et al.22 found that CNS metastatic disease in EGFR-mutant lung cancers was better controlled with targeted therapy than with chemotherapy. Conversely, no targeted therapy is currently approved for HER2-mutant lung cancers.
There are several limitations to this study. Divergent co-mutations and variations of driver mutations resulted in population heterogeneities that may have affected the clinical course of the cancers within each cohort. Due to the relative rarity of HER2-mutant lung cancers, a wider date range (2007 to 2017) was needed to acquire a sufficient sample of patients with HER2-mutant lung cancers than for patients with the more common EGFR- and KRAS-mutant forms of lung cancers (2014 to 2017); this may have introduced a survival bias based on non-evaluated changes in standards of care. This study was not designed to determine the causality of differences in baseline brain metastases or development of brain metastases while on treatment. Given that the baseline rates of metastasis were similar among patients with EGFR-, KRAS-, and HER2-mutant lung cancers, other factors including differences in treatment regimens and standard-of-care CNS surveillance practices may have influenced the rate of brain metastases and introduced possible confounding variables. Too few patients with leptomeningeal disease were noted to be analyzed in this study, and further investigation into this unique subset of brain metastatic disease is warranted.
Conclusion
This study shows that HER2-mutant lung cancers have a clinical course with a high incidence of brain metastases, which is associated with worse survival outcomes. This finding provides a framework for CNS surveillance and treatment strategies, including radiotherapy, for patients with HER2-mutant lung cancers, and underlines the urgent need for the development of novel HER2-targeted agents with activity in the CNS.
Supplementary Material
Acknowledgments:
Funding: This work was supported by the National Institutes of Health/NCI Cancer Center Support Grant [P30 CA008748] and the Eloise Briskin Foundation. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.
Footnotes
Disclosures
Daniel Feldman, Ai Ni, Mackenzie Myers, W. Victoria Lai, Mariza Daras, Adrienne Boire, Emmet J. Jordan, David R. Jones, James M. Isbell, and Viviane Tabar report no disclosures.
Michael Offin received honoraria from PharmaMar, Novartis, and Targeted Oncology.
Elena Pentsova is a consultant for AstraZeneca.
Lisa M. DeAngelis is a consultant for Pharmaco-Kinesis, Genentech, Roche, Sapience Therapeutics, and Juno Therapeutics.
David B. Solit is a consultant for, and received honoraria from, Pfizer and Loxo Oncology.
Maria E. Arcila received speaker’s fees from RainDance Technologies.
Kathryn Beal has stock with MMT pharmaceuticals.
Robert J. Young is a consultant for, and received research funding from, Agios. Dr. Young also has stock or ownership with Agios, Alexion Pharmaceuticals, Biogen Idec, Celgene, Gilead Sciences, Karyopharm Therapeutics, Spark Therapeutics, Regeneron Pharmaceuticals, Stemline Therapeutics, and Vertex Pharmaceuticals.
Charles M. Rudin is a consultant for Abbvie, Amgen, Ascentage, AstraZeneca, Bicycle, Celgene, Chugai, Daiichi Sankyo, Genentech/Roche, GI Therapeutics, Loxo, Novartis, Pharmamar, and Seattle Genetics, and serves on the Scientific Advisory Boards of Elucida and Harpoon.
Gregory J. Riely received research funding from Novartis, Roche, Genentech, Millenium, GlaxoSmithKline, Pfizer, Infinity Pharmaceuticals and ARIAD, travel expenses from Merck Sharp & Dohme, and is listed as inventor on a patent application submitted for pulsatile use of erlotinib to treat or prevent brain metastases.
Alexader Drilon has received honoraria from Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint, Genentech/Roche, Takeda/Ariad/Millenium, Helsinn, Beigene, BergenBio, Hengrui, Exelixis, Bayer, and Tyra Bioscences, institutional research funding from Foundation Medicine, Pfizer, Exelixis, GlaxoSmithKline, Teva, Eli Lily, and Taiho, and royalties from Wolters Kluwer. Minor disclosures include MORE Health (consulting honoraria) and Merck (food/beverage).
Helena Yu is a consultant for AstraZeneca, received travel support from Lilly, and received institutional research funding from Astellas Pharma, AstraZeneca, Daiichi, Lilly, Novartis and Pfizer for clinical trials she is involved in. She is listed as inventor on a patent application submitted for pulsatile use of erlotinib to treat or prevent brain metastases.
Mark G. Kris has received consulting fees from AstraZeneca, Pfizer, and Regeneron, honoraria for participation in educational programs from WebMD, OncLive, Physicians Education Resources, AstraZeneca, and Research to Practice. Dr. Kris is an employee of Memorial Sloan Kettering. Memorial Sloan Kettering has received research funding from Genentech Roche and PUMA Biotechnology for trials conducted by Dr. Kris. Memorial Sloan Kettering has a collaboration for the development of Watson for Oncology with IBM and receives royalties from IBM for this activity.
Bob T. Li is a consultant for Genentech Roche, Thermo Fisher Scientific and Guardant Health.
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