Phase I Study of the BRAF Inhibitor Vemurafenib in Combination With the Mammalian Target of Rapamycin Inhibitor Everolimus in Patients With BRAF-Mutated Malignancies

Abstract

Purpose

Parallel activation of the phosphatidylinositol 3-kinase–mammalian target of rapamycin pathway represents a mechanism of primary and acquired resistance to BRAF-targeted therapy, but the two pathways have yet to be cotargeted in humans. We performed a phase I study to evaluate the safety and activity of the BRAF inhibitor vemurafenib in combination with the mammalian target of rapamycin inhibitor everolimus in BRAF-mutated advanced solid tumors.

Patients and Methods

We performed a 3+3 dose-escalation study with escalating doses of both oral (PO) vemurafenib administered twice a day and PO everolimus administered daily.

Results

Twenty patients with advanced cancers were enrolled. The median adult age was 64 years (range, 17 to 85 years); two pediatric patients were 10 and 13 years old. Patients were heavily pretreated with prior BRAF or MEK inhibitors (n = 11), phase I clinical trial therapy (n = 10), surgery (n = 18), radiation therapy (n = 11), and chemotherapy (n=13). One of the two pediatric patients initially experienced grade 3 rash, but after dermatologic intervention, the patient remains on trial with partial response and no dose reduction at time of analysis. Four dose-limiting toxicities (rash, n = 1; fatigue, n = 3) were observed at dose level 2. Therefore, dose level 1 (vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily) was the maximum-tolerated dose. Overall, four patients (22%) had a partial response and nine patients (50%) had stable disease as best response. One pediatric patient with pleomorphic xanthroastrocytoma remains on protocol with continued clinical response after 38 cycles.

Conclusion

The combination of vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily is safe and well tolerated and has activity across histologies, with partial responses noted in advanced non–small-cell lung cancer, melanoma, optic nerve glioma, and xanthroastrocytoma, including patients who previously experienced progression on BRAF and/or MEK inhibitor therapy. Further investigation in a larger cohort of molecularly matched patients is warranted.

INTRODUCTION

The BRAF oncogene is mutated in > 50% of cutaneous melanomas and in 4% to 10% of nonmelanoma cancers such as non–small-cell lung cancer (NSCLC), colorectal cancer, thyroid cancer, gliomas, and cholangiocarcinomas.^1,2 In many of these tumors, mutations at BRAF^V600 are associated with an aggressive phenotype and decreased progression-free survival (PFS) and overall survival (OS).^3,4 BRAF-targeted therapies such as vemurafenib, dabrafenib, trametinib, and cobimetinib have demonstrated response rates of 50% to 70% and improvements in OS in metastatic melanoma, leading to US Food and Drug Administration and European Medicines Agency approval.⁵ Recently, the combination of dabrafenib and trametinib was approved in NSCLC⁶ and anaplastic thyroid cancer.⁷ However, no US Food and Drug Administration–approved agents exist for BRAF-mutated nonmelanoma cancers aside from NSCLC and anaplastic thyroid cancer. A recent basket study of vemurafenib demonstrated clinical activity in patients with advanced nonmelanoma cancers.⁸ Unfortunately, many patients exhibited primary and acquired resistance to therapy.

Reactivation of MAPK signaling and activation of alternative parallel signaling pathways such as the phosphatidylinositol 3-kinase (PI3K)–mammalian target of rapamycin (mTOR) pathway have been hypothesized to contribute to primary and acquired resistance to BRAF-targeted therapy.^9,10 Specifically, Akt mutation,⁹ PTEN deficiency,¹¹ and downstream mTOR activation have been implicated in resistance to both vemurafenib and dabrafenib in metastatic melanoma, both clinically and in preclinical models.^12,13 Preclinical studies have demonstrated efficacy in dual targeting of both the MAPK and PI3K-mTOR pathways in various tumor types.^14,15 We also recently identified a strong association between co-occurring PI3K-mTOR pathway aberrations and primary resistance to BRAF-targeted therapy. PI3K-mTOR pathway aberrations were associated with a statistically significant reduction in PFS (hazard ratio, 15.0; 95% CI, 3.6 to 63.0; P < .001) and OS (hazard ratio, 19.2; 95% CI, 3.7 to 100.0; P < .001).¹⁶ In addition, others have demonstrated an association between loss-of-function PTEN alterations and resistance to BRAF-targeted therapy in metastatic melanoma.¹⁷ On the basis of this rationale, we designed a phase I dose-escalation trial combining the BRAF inhibitor vemurafenib with the mTOR inhibitor everolimus in all advanced cancers harboring a BRAF mutation. Herein, we report the safety, tolerability, maximum-tolerated dose (MTD), and clinical activity of this combination in patients with advanced cancers.

PATIENTS AND METHODS

Patients

This study was an investigator-initiated, nonrandomized, open-label, dose-escalation phase I clinical trial of vemurafenib and everolimus (ClinicalTrials.gov identifier: NCT01596140) performed at The University of Texas MD Anderson Cancer Center under a protocol approved by the cancer center’s Institutional Review Board (Protocol No. 2012-0153). We enrolled patients with histologically confirmed metastatic or locally advanced BRAF-mutated tumors. All patients were treated at the Clinical Center for Targeted Therapy at The University of Texas MD Anderson Cancer Center from September 2013 to August 2015 and met all the eligibility criteria. All patients had disease that had progressed despite standard therapy or had no available therapy that would increase survival by at least 3 months. Other inclusion criteria included an Eastern Cooperative Oncology Group performance status of 0 to 3 and adequate organ function, including an absolute neutrophil count ≥ 1,000/µL, a platelet count ≥ 50,000/µL, a total bilirubin level less than twice the upper limit of normal, an ALT level < 2.5 times the upper limits of normal, and a creatinine level ≤ 2.0 mg/dL. Patients who had a myocardial infarction within 3 months before starting treatment, who were pregnant or breastfeeding, or who had undergone a major surgical procedure within 28 days were excluded. Palliative radiation therapy was allowed during the study treatment.

Study Design and Treatment

This study was a nonrandomized, open-label, standard 3+3 dose-escalation study of oral (PO) vemurafenib, starting at a dose of 720 mg daily, and PO everolimus, starting at a dose of 5 mg daily, for 28 days. The dose-escalation design is provided in Table 1. The primary objectives were to determine the safety, MTD, and dose-limiting toxicity (DLT) of the combination of vemurafenib and everolimus in patients with BRAF-mutated advanced cancer. The secondary objective was to describe the antitumor efficacy of the drug combination. All participants provided informed consent before entering the study.

Table 1.

Planned Dose Schedule in Patients Who Received the Combination of Vemurafenib and Everolimus in a Phase I Study

An expansion cohort was treated at the MTD. Two pediatric patients were enrolled onto this study and were treated with vemurafenib PO 480 mg daily and everolimus PO 2.5 mg daily, per body surface area–based dose adjustment.

If a patient experienced new grade 3 or greater toxicity, treatment was withheld until the condition was addressed and it recovered to grade 1 or baseline. Treating physicians were then allowed to reduce the dose by up to 50% if the toxicity was attributed to either or both of the study drugs. The patients continued treatment until they experienced disease progression or intolerable toxicities, until the treating physician or patient felt that it was not in the patient’s best interest to continue for any reason, or until consent was withdrawn for any other reason.

All patients were evaluated for DLTs during the first 28 days and evaluated in clinic every 28 days before initiation of each subsequent cycle. The MTD was defined as the highest dose at which no more than 33% of patients developed DLTs. DLTs were treatment-related grade 3 or 4 nonhematologic toxicities, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0, or grade 4 hematologic toxicities lasting > 7 days or accompanied by fever or bleeding during the first 4 weeks of therapy. Medically controlled grade 3 toxicities, including hyperglycemia, nausea, vomiting, diarrhea, and rash, were excluded from the DLTs. Clinical Laboratory Improvement Amendments (CLIA)–certified next-generation sequencing data were collected for each patient.

Response to therapy was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Median time to disease progression and OS duration were determined using the Kaplan-Meier method.

Circulating Tumor DNA

Three patients agreed to have an optional blood draw to measure circulating tumor DNA (ctDNA) at baseline and at each restaging. Whole blood was collected in EDTA–containing tubes and centrifuged and spun twice within 2 hours to yield plasma. The QIAamp Circulating Nucleic Acid kit (Qiagen, Hilden, Germany) was used to isolate cell-free DNA according to the manufacturer’s instructions. At least 8 ng of unamplified cell-free DNA were tested with a droplet digital polymerase chain reaction BRAF^V600E mutation–specific assay and/or multiplex BRAF^V600 Screening Kit (Bio-Rad, Hercules, CA) to distinguish the wild-type allele from the three most common mutations (BRAF^V600E, BRAF^V600K, and BRAF^V600R) using the QX200 Droplet Digital PCR System (Bio-Rad) according to the manufacturer’s standard protocol. The lower limit of detection was approximately 0.2% mutant allele frequency for the multiplexed screening assay and < 0.1% mutant allele frequency per single well for the mutation-specific assays.

RESULTS

Patient Characteristics

The demographics and clinical characteristics of the 20 patients who received at least one dose of vemurafenib and everolimus and completed the DLT window are listed in Table 2. Fourteen males and six females were enrolled onto this study. The most common tumor types were melanoma (n = 7), glioma (n = 5), and thyroid cancer (n = 4), and one patient each had appendiceal cancer, colorectal cancer, NSCLC, and unknown primary cancer. The median age of the 18 adult patients was 64 years; two pediatric patients were age 10 and 13 years old. Patients were heavily pretreated with prior therapies, including BRAF or MEK inhibitor therapy (n = 11), prior phase I clinical trial therapy (n = 10), surgery (n = 18), radiotherapy (n = 11), and chemotherapy (n = 13). One patient had measurable disease but not evaluable disease, and a second patient was not evaluable as a result of withdrawing consent before the first restaging, but both patients cleared the toxicity window and therefore are included in the toxicity evaluation but not in the response evaluation.

Table 2.

Demographic Characteristics of Patients Treated With Vemurafenib and Everolimus

Safety

All 20 patients were evaluated for DLTs. One of the two pediatric patients initially experienced a grade 3 rash, but after dermatologic intervention, the patient was able to continue on trial without dose reduction and remains on trial with partial response (PR) at time of analysis. The second pediatric patient experienced no toxicity. No DLTs were observed in the adult patients treated on dose level 1 during the dose-escalation phase. Four DLTs (one patient with rash and three patients with fatigue) were observed at dose level 2 (Table 3). Therefore, dose level 1 (vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily) was determined to be the MTD. All grade 3 and 4 toxicities experienced during dose escalation and dose expansion are listed in Appendix Table A1. Overall, fatigue was the most common grade 3 toxicity (n = 4), followed by rash (n = 3). In addition, one patient each experienced grade 3 anemia, thrombocytopenia, hyperglycemia, and hypertriglyceridemia. Six patients (30%) required dose modifications. Five patients (25%) had everolimus dose reductions throughout their therapy as a result of toxicity, and one patient had the vemurafenib dose reduced as a result of renal insufficiency. Two patients without DLTs withdrew consent before disease progression.

Table 3.

DLTs Observed in Patients Treated With Vemurafenib and Everolimus

Response

Of the 18 patients evaluable for response, 11 patients (61%) had objective tumor volume reduction as best response. Overall, four patients (22%) had a PR and nine patients (50%) had stable disease as best response, per RECIST 1.1. A waterfall plot illustrating response in all evaluable patients is shown in Figure 1A. Two patients were not evaluable for response; one patient had measurable but not evaluable disease and a second patient completed the DLT window but withdrew consent before restaging.

Fig 1.

(A) Waterfall plot depicting best response as percent change in target lesions in all 18 evaluable patients with advanced cancer treated with vemurafenib and everolimus. Patients previously treated with a BRAF and/or MEK inhibitor are in blue. Stars indicate patients still on trial without disease progression at the time of analysis. (B) Representative restaging images of a patient with metastatic melanoma and a PTEN (P95S) mutation who had a partial response on vemurafenib and everolimus after disease progression on vemurafenib and PX866, an investigational PI3K inhibitor. Astro, anaplastic astrocytoma; AT, anaplastic thyroid; CRC, colorectal cancer; CUP, cancer of unknown primary; Glio, glioblastoma; Glioma, optic nerve glioma; Mel, melanoma; PT, papillary thyroid.

PRs were seen in patients with NSCLC, melanoma, optic nerve glioma, and pleomorphic xanthroastrocytoma. Five patients had progression of disease at or before first restaging. All five nonresponders were either previously treated with BRAF or MEK inhibitors or harbored non-V600 BRAF mutations. Of the nine patients who had disease progression on BRAF or MEK inhibitors before enrolling onto this study, two (22%) had PRs and five (56%) had stable disease with vemurafenib and everolimus.

At the time of analysis, 14 patients (78%) had discontinued therapy because of disease progression. Other reasons for study discontinuation included toxicity (n = 2, 11%) and withdrawal of consent (n = 2, 11%). One pediatric patient with pleomorphic xanthroastrocytoma remains on protocol with continued clinical response after 38 cycles.

Genomic Profiling

All evaluable patients underwent CLIA-certified clinical next-generation sequencing of at least 50 genes before trial enrollment. Among the four patients who achieved PR, a patient with metastatic melanoma who had previously experienced progression on vemurafenib plus an investigational PI3K inhibitor (PX866) had a concurrent PTEN (P95S) mutation. A patient with NSCLC whose tumor harbored an IDH1 (R132C) mutation, ARID2 alteration (splice site 92+1 G>A), and PPP1R2A mutation (R183W) achieved a PR after previously experiencing progression on dabrafenib. The remaining two patients who achieved PR had no concurrent molecular aberrations other than the BRAF^V600E mutation. A treatment-naive patient with papillary thyroid cancer who had stable disease (27% tumor reduction) for 7 months had a co-occurring PIK3CA H1047R mutation. All concurrent molecular aberrations and best response to therapy for each patient are listed in Table 4.

Table 4.

Tumor Type, Molecular Aberrations, and Best Response Observed in Patients Who Received the Combination of Vemurafenib and Everolimus in a Phase I Study

Circulating Tumor DNA

Patients enrolled onto this study were offered an optional blood draw to measure ctDNA throughout the course of the study. Three patients provided written consent for this blood sample and had it drawn at baseline and at each restaging. One patient with BRAF-mutated metastatic colorectal cancer and a second patient with BRAF-mutated papillary thyroid cancer only had wild-type BRAF identified on ctDNA. A third patient with a BRAF^V600E mutation had detectable ctDNA levels, which were measured at four time points throughout therapy and are depicted in Figure 2 alongside the patient’s scans. At baseline before initiating therapy with vemurafenib plus everolimus, the patient had 608 copies/mL of mutated BRAF^V600E. At first restaging, the patient had a 37% reduction in tumor target lesions, which corresponded with a reduction in detectable mutated BRAF^V600E to 47 copies/mL. An interim blood draw after this restaging demonstrated an increase in detectable mutated BRAF^V600E to 195 copies/mL before the patient’s next restaging, which demonstrated disease progression per RECIST 1.1 with new metastatic lesions, and this corresponded with a continued increase in detectable mutated BRAF^V600E to 320 copies/mL.

Fig 2.

Graphical depiction of a patient’s circulating tumor DNA level of BRAF^V600E (shown as copies per milliliter of plasma) while on treatment with vemurafenib plus everolimus with representative restaging scans and response to therapy, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. PD, progression of disease; PR, partial response.

DISCUSSION

A concerted effort to genomically characterize treatment-refractory cancers has led to the identification of a number of shared actionable mutations across tumor histologies, such as the BRAF mutation. However, it remains difficult to predict which patients harboring a BRAF mutation will respond to BRAF-targeted therapy. Moreover, responses are often brief and subsequently followed by the development of resistance to therapy. Preclinical data suggest concurrent mTOR inhibition can overcome resistance to BRAF-targeted therapy,^14,15 but human safety and efficacy studies of the combination of vemurafenib and everolimus had to be performed before this study.

One of the major challenges of combining tyrosine kinase inhibitors is overlapping toxicities.^18,19 Our trial demonstrates that the combination of vemurafenib and everolimus can be tolerated in patients with advanced malignancies. DLTs included fatigue (20%) and rash (15%), but both were present in only one patient at the MTD and recommended phase II dose of vemurafenib 720 mg twice daily and everolimus 5 mg daily. This is not surprising because two common adverse effects of both single-agent vemurafenib and single-agent everolimus are fatigue and rash. The patient with glioblastoma who experienced a grade 3 rash had a resolution of his rash after initial everolimus discontinuation and was able to resume everolimus at a dose of 2.5 mg daily without toxicity. The patient with melanoma with grade 3 fatigue required only a brief treatment break before resuming treatment at the MTD. The use of nonpharmacologic approaches, such as physical and mindfulness-based exercise therapy,^20,21 and pharmacologic approaches, such as corticosteroids²² in treating cancer- and therapy-related fatigue, has recently demonstrated efficacy in randomized controlled trials and may benefit these patients moving forward.

We observed only one metabolic adverse event (hypertriglyceridemia and hyperglycemia), which is attributed to mTOR inhibitors. This patient had metabolic risk factors, including morbid obesity, hypertension, and hyperlipidemia, before enrollment. Similarly, only one patient each had grade 3 anemia and thrombocytopenia in this study, and both patients had been heavily pretreated with cytotoxic chemotherapy. Overall, most patients at the recommended phase II dose tolerated the treatment well.

Our trial also demonstrates that the addition of an mTOR inhibitor to everolimus treatment is able to overcome resistance to BRAF and/or MEK inhibition in a subset of patients with BRAF-mutant advanced cancers. Four of the 20 patients in this study had a PR to therapy. Notably, two of these four patients had previously experienced progression on a BRAF inhibitor. A patient with NSCLC who had previously experienced progression on treatment with single-agent dabrafenib after multiple lines of standard-of-care chemotherapy had a PR. Next-generation sequencing performed at the time of initial diagnosis revealed IDH1 (R132C), ARID2 (splice site 92+1 G>A), and PPP1R2A (R183W) aberrations. Unfortunately, no molecular profiling was available at the time the patient experienced progression on dabrafenib immediately before enrolling onto this trial.

A second patient with metastatic melanoma and a PTEN (P95S) mutation who had recently had disease progression on vemurafenib and PX866, an investigational PI3K inhibitor, also achieved a PR on our trial (Fig 1B). PI3K inhibitors are synergistic with vemurafenib preclinically and demonstrate decreased cell proliferation and increased apoptosis in PTEN-deficient, BRAF-mutated melanoma cell lines in vitro. In vivo, PTEN-deficient, BRAF-mutated mouse models treated with vemurafenib and PI3K inhibitors also demonstrate synergistic antitumor activity.²³ Interestingly, this patient experienced progression on the vemurafenib and investigational PI3K inhibitor combination but responded with a PR to vemurafenib and everolimus. This highlights the complexities of oncogenic signaling in humans that are not always reflected in preclinical models. A 78-year-old patient with metastatic papillary thyroid cancer whose tumor harbored a PIK3CA (H1047R) mutation had 7 months of stable disease with a 27% reduction in tumor burden before having any disease progression. However, neither of the other two patients with papillary thyroid cancer on this trial had as robust or durable of a response. Both of these patients had no co-occurring genomic alterations identified on their tumors other than the BRAF^V600E mutation, illustrating the fact that although co-occurring alterations may lead to activation of parallel signaling pathways that increase resistance to therapy in some patients, they may render other tumors susceptible to therapy when actionable.

We have previously reported our institution’s experience with implementing multiplex hotspot testing and the need to enroll patients onto genotype-matched trials when feasible.²⁴ A number of the responders on this trial further support the hypothesis that the identification of actionable alterations can help guide the right patient to the right targeted therapy. All nonresponders were either previously treated with BRAF or MEK inhibitor or harbored non-V600 BRAF mutations.

In the patient with metastatic melanoma with measurable ctDNA, the level of mutated BRAF^V600E copies per milliliter decreased with clinical response and increased before subsequent restaging that demonstrated disease progression. Prior studies have suggested that longitudinal ctDNA dynamics may correlate with treatment response in both melanoma and breast cancer.^25,26 This patient’s ctDNA dynamics support that hypothesis. The other two patients who consented for ctDNA analysis did not have detectable mutated BRAF^V600E using our assay. Previous studies have identified an association between detection and levels of circulating tumor DNA and disease burden and survival across BRAF and MEK inhibitor trials.²⁷ It is plausible that this may explain why only wild-type BRAF was detectable in the plasma of these two patients.

Our study has several limitations, including a small patient population and the variety of molecular profiling platforms used. Although all patients underwent CLIA-certified next-generation sequencing of at least 40 genes, including those in the PI3K-mTOR pathway, some patients underwent more extensive 400-gene profiling. Ideally, all patients should have a broader panel of testing to identify all actionable aberrations, both at the time of study initiation and at disease progression, to better understand the clonal evolution of tumors treated with vemurafenib and everolimus. Biopsying each patient at progression would have been challenging at the time of the study, but as methods to peripherally evaluate mutational load with ctDNA become validated and readily available in the near future, this will become more feasible.²⁸

MEK mutation is known to confer resistance to BRAF-targeted monotherapy,²⁹ and the combination of BRAF and MEK inhibition improves OS compared with BRAF inhibition alone in metastatic melanoma.³⁰ Recent preclinical in vitro data suggest that the combination of MEK and mTOR inhibition may be more effective than BRAF and mTOR inhibition in activating Bax and caspase-3 and inducing caspase-dependent apoptosis in melanoma cell lines.³¹ Future studies to investigate the safety and effectiveness of combining everolimus with both BRAF and MEK inhibitors together are being planned.

In conclusion, the combination of vemurafenib and everolimus is safe and well tolerated and has clinical activity across histologies, with PRs noted in patients with advanced NSCLC, melanoma, optic nerve glioma, and xanthroastrocytoma. Studies to identify the proper selection and timing of patients with BRAF-mutated tumors who would benefit from the addition of an mTOR inhibitor are ongoing. Our results do not support the addition of everolimus based solely on alterations in the PI3K-mTOR pathway; however, given the responders who did harbor concurrent mutations in this pathway, further investigation in a larger cohort of molecularly matched patients with uniform genomic profiling is warranted. Our results support a combinatorial targeted approach in appropriately selected patients.

Appendix

Table A1.

All Grade 3 and 4 Toxicities Observed in Patients Treated With Vemurafenib and Everolimus

AUTHOR CONTRIBUTIONS

Conception and design: Vivek Subbiah, Shiraj Sen, Filip Janku, Javier Munoz, Apostolia M. Tsimberidou, Steven I. Sherman, Patrick Hwu

Administrative support: Patrick Hwu

Provision of study material or patients: Filip Janku, David S. Hong, Gerald S. Falchook, Apostolia M. Tsimberidou, Patrick Hwu

Collection and assembly of data: Vivek Subbiah, Shiraj Sen, Filip Janku, David S. Hong, Daniel D. Karp, Javier Munoz, Gerald S. Falchook, Apostolia M. Tsimberidou, Steven I. Sherman, Patrick Hwu, Funda Meric-Bernstam

Data analysis and interpretation: Vivek Subbiah, Shiraj Sen, Kenneth R. Hess, Filip Janku, Soumen Khatua, Javier Munoz, Gerald S. Falchook, Roman Groisberg, Steven I. Sherman, Patrick Hwu

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Vivek Subbiah

Consulting or Advisory Role: MedImmune

Research Funding: Novartis (Inst), GlaxoSmithKline (Inst), NanoCarrier (Inst), Northwest Biotherapeutics (Inst), Genentech (Inst), Berg Pharma (Inst), Bayer (Inst), Incyte (Inst), Fujifilm (Inst), PharmaMar (Inst), D3 Oncology Solutions (Inst), Pfizer (Inst), Amgen (Inst), AbbVie (Inst), Multivir (Inst), Blueprint Medicines (Inst), Loxo (Inst), Vegenics (Inst), Takeda (Inst), Alfasigma (Inst), Agensys (Inst), Idera (Inst), Boston Biomedical (Inst)

Travel, Accommodations, Expenses: PharmaMar, Bayer

Shiraj Sen

No relationship to disclose

Kenneth R. Hess

No relationship to disclose

Filip Janku

Stock and Other Ownership Interests: Trovagene

Consulting or Advisory Role: Deciphera, Trovagene, Novartis, Sequenom, Foundation Medicine, Guardant Health, Immunome

Research Funding: Novartis, BioMed Valley Discoveries, Roche, Agios, Astellas Pharma, Deciphera, Symphony Evolution, Plexxikon, Piqur, Fujifilm

Other Relationship: Bio-Rad

David S. Hong

Stock and Other Ownership Interests: MolecularMatch, Oncorena

Honoraria: Adaptimmune, Baxter, Merrimack, Bayer

Consulting or Advisory Role: Baxter, Bayer, Guidepoint Global, Janssen

Speakers' Bureau: Genentech, Janssen Oncology

Research Funding: Novartis, Genentech, Eisai, AstraZeneca, Pfizer, miRNA Therapeutics, Amgen, Daiichi Sankyo, Merck, Mirati Therapeutics, Eli Lilly, Adaptimmune, AbbVie, Bayer, Bristol-Myers Squibb, Genmab, Ignyta, Infinity Pharmaceuticals, Kite Pharma, Kyowa Hakko Kirin, Loxo, MedImmune, Molecular Templates, Takeda

Travel, Accommodations, Expenses: Loxo, miRNA Therapeutics

Other Relationship: Oncorena, Eisai

Soumen Khatua

No relationship to disclose

Daniel D. Karp

Consulting or Advisory Role: Black Beret Life Sciences

Research Funding: Phosplatin Therapeutics

Travel, Accommodations, Expenses: Phosplatin Therapeutics

Javier Munoz

Consulting or Advisory Role: Kite Pharma, Pfizer, Pharmacyclics, Bayer, Alexion Pharmaceuticals, Bristol-Myers Squibb, Janssen, Seattle Genetics, Gilead Sciences, Kyowa Hakko Kirin

Speakers' Bureau: Kite Pharma

Gerald S. Falchook

Employment: Sarah Cannon Research Institute, HealthONE

Research Funding: Millennium, EMD Serono, Celgene, MedImmune, Genmab, Vegenics, Novartis, AstraZeneca, Incyte, ARMO BioSciences, Kolltan Pharmaceuticals, 3-V Biosciences, AbbVie, Aileron Therapeutics, DelMar Pharmaceuticals, eFFECTOR Therapeutics, Strategia Therapeutics, Fujifilm, Hutchison MediPharma, Regeneron, Biothera, Curegenix, Curis, Eli Lilly, Jounce Therapeutics, OncoMed, Precision Oncology, Syndax, Taiho Pharmaceutical, Tesaro, Takeda, BeiGene, Ignyta, Merck, Rgenix, Tarveda Therapeutics, Tocagen

Patents, Royalties, Other Intellectual Property: Handbook of Targeted Cancer Therapy

Travel, Accommodations, Expenses: Millennium, Sarah Cannon Research Institute, EMD Serono, Bristol-Myers Squibb

Roman Groisberg

No relationship to disclose

Apostolia M. Tsimberidou

Consulting or Advisory Role: Roche

Research Funding: EMD Serono (Inst), Baxter (Inst), Foundation Medicine (Inst), Onyx (Inst), Bayer (Inst), Boston Biomedical (Inst), Placon (Inst), IMMATICS (Inst), Karus Therapeutics (Inst), Stem Cells (Inst), OBI Pharma (Inst)

Steven I. Sherman

Honoraria: Genzyme, Eisai

Consulting or Advisory Role: Eisai, Exelixis, Veracyte, Novo Nordisk, Bristol-Myers Squibb, Loxo, Genzyme, Ignyta, Novartis

Research Funding: Genzyme

Travel, Accommodations, Expenses: Eisai, Veracyte, Ignyta

Patrick Hwu

Stock and Other Ownership Interests: Immatics

Consulting or Advisory Role: Dragonfly Therapeutics, GlaxoSmithKline, Immatics, Sanofi

Research Funding: Genentech (Inst)

Funda Meric-Bernstam

Honoraria: Sumitomo Group, Dialectica

Consulting or Advisory Role: Genentech, Inflection Biosciences, Pieris Pharmaceuticals, Clearlight Diagnostics, Darwin Health, Samsung Bioepis, Spectrum Pharmaceuticals

Research Funding: Novartis, AstraZeneca, Taiho Pharmaceutical, Genentech, Calithera Biosciences, Debiopharm Group, Bayer, Aileron Therapeutics, PUMA Biotechnology, CytomX Therapeutics, Jounce Therapeutics, Zymeworks, Curis, Pfizer, eFFECTOR Therapeutics, AbbVie