Abstract
Purpose:
Report results of the phase Ib dose-escalation/expansion study of triplet therapy with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor (ribociclib), mTOR inhibitor (everolimus), and endocrine therapy (exemestane).
Patients and Methods:
Postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), pretreated, advanced breast cancer (ABC) were enrolled. The primary objective of the dose-escalation phase was to estimate the MTD and recommended phase II dose (RP2D) of triplet therapy through evaluation of the incidence of dose-limiting toxicities. Safety, tolerability, and efficacy of the RP2D were evaluated in the dose-expansion phase in patients naïve or refractory to CDK4/6 inhibitor therapy.
Results:
Patients (N = 116) received triplet therapy (n = 83 in the dose-escalation phase; n = 33 in the dose-expansion phase). A dose-dependent drug–drug interaction was observed for everolimus, with exposure increasing two- to fourfold in the presence of ribociclib. The RP2D was determined to be ribociclib 300 mg once daily, 3 weeks on/1 week off in a 4-week cycle, plus everolimus 2.5 mg once daily, plus exemestane 25 mg once daily taken with food. The safety profile was consistent with the known profiles of the combination partners, and preliminary evidence of antitumor activity was observed. Higher ESR1 gene expression trended with better treatment response to triplet therapy; higher gene expression of MAPK pathway genes trended with worse treatment response.
Conclusions:
Triplet therapy with endocrine therapy and mTOR and CDK4/6 inhibition provides clinical benefit and an acceptable safety profile in previously treated postmenopausal women with HR+, HER2− ABC.
Introduction
Endocrine therapy (ET) is the preferred treatment option for patients with hormone receptor–positive (HR+), HER 2-negative (HER2−) advanced breast cancer (ABC; refs. 1–3).
The combination of ET with agents that target the cyclin D–cyclin-dependent kinase (CDK) 4/6–retinoblastoma (Rb) pathway and the phosphoinositide 3-kinase (PI3K) signaling pathway has led to improvements in outcomes for patients with HR+, HER2− ABC (4–7). The combination of ribociclib [a CDK4/6 inhibitor (CDK4/6i)] with ET is associated with significant improvements in progression-free survival (PFS) (8, 9) and overall survival (10, 11).
Everolimus is a derivative of rapamycin that inhibits mammalian target of rapamycin (mTOR), one of the downstream nodes of the PI3K signaling pathway; its addition to exemestane, an aromatase inhibitor (AI), significantly improves PFS versus exemestane alone in postmenopausal women with ABC after failure of treatment with a nonsteroidal AI (5, 12, 13).
Despite the demonstrated efficacy of these treatment combinations, most patients with HR+, HER2− ABC eventually experience disease progression due to endocrine resistance; therefore, the prevention of treatment resistance in this setting constitutes an unmet medical need (6, 14).
Cross-talk between the estrogen receptor (ER), the CDK4/6 pathway, and thePI3K pathway is associated withendocrine resistance, and activation of the PI3K pathway has been reported as one of the potential mechanisms of resistance to CDK4/6 inhibition, thus providing rationale for combined inhibition of the CDK4/6 and PI3K signaling pathways (15).
Preclinical data suggest that triple combination of ribociclib, everolimus, and fulvestrant may help to prevent resistance to ribociclib and in inducing tumor growth regression in xenograft models with acquired resistance to CDK4/6is (16, 17). It was reported that the development of resistance to CDK4/6 inhibition may occur through the loss of dependence on Rb-related signaling and activation of alterative signaling pathways; therefore, targeting alternative pathways such as the PI3K pathway could be a potential strategy to overcome CDK4/6 inhibition resistance (15, 18, 19). These results provide a strong rationale for investigating in a clinical study whether the approved combination of everolimus with exemestane could be enhanced by the addition of ribociclib.
Here we report on the safety, pharmacokinetics, and preliminary efficacy of triplet therapy with ribociclib, everolimus, and exemestane from a phase Ib study in postmenopausal women with HR+, HER2− ABC (funded by Novartis; CLEE011X2106 ClinicalTrials.gov number, NCT01857193).
Patients and Methods
This open-label, multicenter, phase Ib study consisted of:
A dose-escalation phase to estimate the MTD and recommended phase II dose (RP2D) of triplet therapy with ribociclib, everolimus, and exemestane in postmenopausal women with ER+, HER2− ABC
A dose-expansion phase to characterize the safety, tolerability, and preliminary efficacy of the RP2D of triplet therapy in postmenopausal women with HR+, HER2− ABC who were resistant to previous therapy with nonsteroidal AI; defined as recurrence during or within ≤12 months from the end of adjuvant treatment or progression during or ≤1 month after stopping treatment for advanced disease
Study oversight
The study was designed, implemented, and reported in accordance with the ethical principles laid down in the Declaration of Helsinki. The study protocol and all amendments were reviewed by the Independent Ethics Committee or Institutional Review Board for each center. Informed consent was obtained from each patient in writing before screening procedures. The study was described by the investigator and/or designated staff, who answered any questions, and written information was also provided.
Patient population
Key inclusion criteria included postmenopausal and adult women (≥18 years of age) with HER2− locally advanced or metastatic breast cancer not amenable to curative treatment by surgery or radiotherapy who experienced recurrence during, or within 12 months of ending, adjuvant treatment with letrozole or anastrozole; or progression during, or within 1 month of stopping, letrozole or anastrozole treatment for ABC, with radiological or objective evidence of recurrence or progression on or after the last systemic therapy prior to enrollment. Local histologic or cytologic confirmation of ER+ breast cancer (dose escalation) and HR+ breast cancer (dose expansion) was required. A representative tumor specimen available for exploratory biomarker analysis from patients in both phases of the study was requested (not mandatory) and analyzed, when available. In the dose-escalation groups, patients were required to have measurable or only nonmeasurable lesions (e.g., pleural effusion, ascites, any bone lesions; RECIST; ref. 19), whereas in the dose-expansion groups, patients were required to have ≥1 measurable lesion or lytic/mixed bone lesions in the absence of measurable disease. Prior treatment with chemotherapy for ABC was permitted but was restricted to ≤2 lines in the dose-escalation phase and ≤1 line in the dose-expansion phase. Additional eligibility criteria included an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤1 and a representative tumor sample (archival or newly obtained) for molecular testing.
Patients were ineligible if they had HER2 overexpression (confirmed via IHC 3+ staining or in situ hybridization-positivity), a history of any brain or other central nervous system metastases; clinically significant, uncontrolled heart disease; and/or recent cardiac repolarization abnormalities. In the dose-expansion phase, patients previously treated with exemestane or an mTOR inhibitor, or who were intolerant toCDK4/6is, AIs, mTOR inhibitors, or any component of them, were not eligible for the study. In the dose-escalation phase, patients previously treated with CDK4/6is, mTOR inhibitors, or exemestane were eligible, unless they had shown intolerance to any of these drugs previously. Patients previously treated with a PI3K inhibitor were eligible for both phases.
Dose and regimen selection
The rationale for the starting dose of ribociclib was based on a review of the safety, tolerability, and pharmacokinetic evaluation between ribociclib doses of 50–1,200 mg (ref. 20; ClinicalTrials.gov number, NCT01237236); the potential for overlapping toxicities (including stomatitis and cytopenias) between ribociclib and everolimus; the uncertainty around the additive toxicities across the three compounds administered together; and Bayesian logistic regression model (BLRM) recommendations. On the basis of escalation with overdose control (EWOC) criteria, the starting dose for ribociclib in the triplet combination was 200 mg once daily given on a 3 weeks on/1 week off schedule, that is, once daily for 21 consecutive days followed by 7 days off treatment, resulting in a complete cycle of 28 days. This starting dose combination fulfilled the EWOC criterion [<25% chance that the true dose-limiting toxicity (DLT) rate was >35%].
As ribociclib is a CYP3A4 inhibitor and everolimus is a CYP3A4 substrate (21, 22), a drug–drug interaction (DDI) was expected. These data suggested that treatment with ribociclib could increase everolimus exposure approximately 3.5-fold; therefore, a starting dose of everolimus 2.5 mg once daily was used. During the dose-escalation phase, the dose of everolimus was adjusted/escalated as guided by the BLRM recommendations based on EWOC criteria, safety data including DLTs, the frequency and severity of adverse events (AEs), tolerability, and pharmacokinetic data. Because ribociclib has low potential for a food effect (23), the starting dose for the fed cohort was the same as for the fasting cohort (ribociclib 200 mg, everolimus 2.5 mg, and exemestane 25 mg).
Successive cohorts of newly enrolled patients received various dose pairs of ribociclib (250 mg, 300 mg, or 350 mg) and everolimus (1 mg or 5 mg), with exemestane at a fixed dose of 25 mg. Exemestane and everolimus are generally given with food, whereas ribociclib can be taken with or without food; therefore, the triplet combination was evaluated in both fasted and fed patients. These groups were enrolled sequentially, with the fasted cohort being enrolled first. Later on, certain dosage groups were selected in the dose-escalation phase to examine food effects at specific dosages. In the dose-expansion phase, dosages were equally matched between groups. For patients enrolled in fasting cohorts, study drugs were administered at least 1 hour before or 2 hours after a meal (Fig. 1).
Figure 1.
Study design. EVE, everolimus; EXE, exemestane; RIB, ribociclib.
Estimation of the MTD of the triplet combination was based on the estimation of the probability of DLT in cycle 1 for patients in the dose-determining set. An adaptive BLRM guided by the EWOC principle regulated the dose escalation. After each cohort of patients was determined, the next recommended dose combination was the one with the highest posterior probability of DLT within the targeted interval (16%–35%), with <25% chance of excessive toxicity. The final recommended MTD/RP2D for each combination treatment was based on the recommendation from the BLRM and on an overall assessment of safety, taking into consideration tolerability data from subsequent cycles at dose combinations tested for this combination treatment. Actual selection of potential combination doses was also influenced by observed everolimus pharmacokinetics in prior cohorts.
Following RP2D declaration for the triplet therapy, patients were enrolled into two treatment groups in the dose-expansion phase, receiving the triplet combination with food at the RP2D. The triplet combination was evaluated in patients naïve or refractory to CDK4/6i therapy (Fig. 1).
Dose adjustments
In cycle 1, if a patient experienced a DLT or a subsequent AE in the dose-escalation phase, treatment with all drugs (ribociclib, everolimus, and exemestane) was to be interrupted. If the toxicity resolved to grade 1 or baseline within 1 week of onset, treatment could be resumed at the same or a lower dose level, at the investigator’s discretion and following discussion with the trial sponsor.
After cycle 1, for toxicities that resulted in treatment delays of >7 but not >21 days, treatment could be resumed at a lower dose level at investigator’s discretion and following discussion with the trial sponsor. If a patient required a dose interruption of >21 days from the intended next scheduled dose, the patient was discontinued. All patients were followed for AEs and serious AEs (SAEs) for 30 days after administration of the final dose of study drug.
Study objective
Dose escalation
The primary objective for the dose-escalation phase was to estimate the MTD and RP2D of triplet therapy by evaluating the incidence of DLTs with triplet therapy in cycle 1.
The secondary objective was the safety and tolerability of the triplet combination, as measured by the incidence and severity of AEs and SAEs, clinical laboratory values, vital signs, electrocardiograms, dose interruptions, dose reductions, and dose intensity.
Determination of the pharmacokinetic profile of ribociclib and everolimus in the triplet combination and evaluation of the DDI potential (effect of ribociclib on the pharmacokinetic profile of everolimus) with food or in the fasted state were also secondary endpoints of the dose-escalation phase.
Dose expansion
The primary endpoint for the dose-expansion phase was safety and tolerability of triplet therapy at the RP2D identified in the dose-escalation phase.
The secondary endpoint was preliminary antitumor activity of triplet therapy observed through efficacy results of overall response rate (ORR), clinical benefit rate (CBR), and PFS. CBR was defined as complete response (CR) plus partial response (PR) plus stable disease (SD) or non-CR/nonprogressive disease (PD) ≥24 weeks. The exploratory biomarker analyses included assessment of baseline gene expression patterns and the potential correlation between gene expression and clinical outcome.
Study assessments
Safety and tolerability
Assessments included all reports of AEs and SAEs. All assessments were performed predose unless otherwise specified, and included hematology, clinical chemistry, urinalysis, hepatitis B virus/hepatitis C virus testing (if positive at baseline), and electrocardiograms. Additional hepatic safety marker monitoring was conducted in the dose-expansion phase of the study. Regular physical examinations were performed, as well as assessments of vital signs, ECOG PS, height, and weight.
Pharmacokinetics
Pharmacokinetic characteristics of ribociclib (and its major metabolite LEQ803) were determined using samples collected from all patients enrolled in the dose-escalation phase. Blood for pharmacokinetic profiling of ribociclib and everolimus was collected on cycle 1 days 1, 2, 8, 15, 16, and 21. In both phases, samples for pharmacokinetic analysis were collected predose and at 1, 2, and 4 hours postdose on days 1and 15 of cycle 1, and predose onday 1of cycles 2–6. Additional pharmacokinetic samples were collected from the dose-escalation phase at the following time points: 0.5, 8, and 24 hours after the first dose; predose and 4 hours postdose on day 8; 0.5, 8, and 24 hours postdose on day 15; and predose on day 21 in cycle 1. Pharmacokinetic sampling for ribociclib and exemestane was performed on days 1 and 15 of cycle 1 and day 1 of cycle 2.
Drug concentration measurements
Plasma concentrations of ribociclib (and LEQ803) were measured using a validated LC/MS-MS assay, with a lower limit of quantitation (LLOQ) of 1.00 ng/mL. Concentrations of everolimus in whole blood were determined by an LC/MS method using an LLOQof 0.300 ng/mL. Plasma concentrations of exemestane were measured using a validated LC/MS-MS assay and an LLOQ of 20 ng/mL.
Efficacy
Tumor response was assessed by RECIST v1.1 (24). Pretreatment CT or MRI scans were required for the chest, abdomen, and pelvis, and if clinically indicated, for the brain and other areas of disease. Whole-body bone assessments were required per institutional standard of care. Subsequent tumor evaluations were performed according to a specified schedule or if clinically indicated. If the last prior tumor evaluation was within 28 days of end of treatment, or objective evidence of PD had already been documented, tumor evaluations were not repeated at end of treatment.
For other radiological assessments (e.g., bone scan, brain CT/MRI), if there was no evidence of disease in a body region at baseline, that region was not imaged at subsequent assessments, unless there was clinical concern for a new lesion in that body region. All radiological assessments obtained for patients enrolled during the dose-escalation and dose-expansion phases were centrally collected and underwent quality checks by an imaging contract research organization selected by Novartis.
Biomarkers
In the CDK4/6i-refractory group, baseline tumor samples were collected prior to study therapy and after disease progression on prior CDK4/6i therapy; archival or fresh tumor specimens were also collected prior to study entry in the CDK4/6i-naïve group. This analysis was exploratory: tumor samples were assessed for mRNA expression using the NanoString 230-gene nCounter GX Human Cancer Reference panel (NanoString). Two-step normalization (positive control and housekeeping gene) was performed on the NanoString raw counts; log2 transformation was performed on the normalized counts.
Results
Patient disposition and baseline characteristics
Between September 6, 2013 and March 14, 2018, a total of 116 patients received triplet therapy of ribociclib plus everolimus plus exemestane across both the dose-escalation and dose-expansion phases (Table 1). Overall, 83 patients received triplet therapy in the dose-escalation phase [group 1 (fasting), n = 41; group 2 (fed), n = 42] and 33 received triplet treatment in the dose expansion phase [group 1 (CDK4/6i-naïve), n = 16; group 2 (CDK4/6i-refractory), n = 17]. The primary reason for treatment discontinuation in both phases of the study was disease progression:
Table 1.
Demographics and characteristics of patients treated with triple combination of ribociclib plus exemestane plus everolimus.
| Demographic variable | Dose-escalation group 1 (fasting) n = 41 |
Dose-escalation group 2 (fed) n = 42 |
Dose-expansion group 1 (CDK4/6i-naïve) n = 16 |
Dose-expansion group 2 (CDK4/6i-refractory) n = 17 |
|---|---|---|---|---|
| Median age, years | 55.0 | 56.5 | 62.0 | 56.0 |
| Sex, n (%) | 41 (100) | 42 (100) | 16 (100) | 17 (100) |
| Race, n (%) | ||||
| White | 32 (78.0) | 33 (78.6) | 13 (81.3) | 14 (82.4) |
| Black | 3 (7.3) | 4 (9.5) | 1 (6.3) | 0 |
| Asian | 4 (9.8) | 4 (9.5) | 0 | 0 |
| Native American | 0 | 0 | 1 (6.3) | 0 |
| Other | 2 (4.9) | 0 | 1 (6.3) | 3 (17.6) |
| Missing | 0 | 1 (2.4) | 0 | 0 |
| Ethnicity, n (%) | ||||
| Hispanic/Latino | 7 (17.1) | 4 (9.5) | 2 (12.5) | 2 (11.8) |
| Chinese | 3 (7.3) | 3 (7.1) | 0 | 0 |
| Other | 28 (68.3) | 29 (69.0) | 12 (75.0) | 15 (88.2) |
| Missing | 3 (7.3) | 6 (14.3) | 2 (12.5) | 0 |
| WHO/ECOG performance status, n (%)a | ||||
| 0 | 19 (46.3) | 21 (50.0) | 11 (68.8) | 11 (64.7) |
| 1 | 22 (53.7) | 21 (50.0) | 5 (31.3) | 6 (35.3) |
| Metastatic site, n (%) | ||||
| CNS | 2 (4.9) | 0 | 1 (6.3) | 2 (11.8) |
| Bone | 32 (78.0) | 36 (85.7) | 13 (81.3) | 11 (64.7) |
| Bone only | 4 (9.8) | 3 (7.1) | 2 (12.5) | 2 (11.8) |
| Visceral | 3 (7.3) | 4 (9.5) | 1 (6.3) | 0 |
| Liver | 27 (65.9) | 25 (59.5) | 4 (25.0) | 10 (58.8) |
| Lung | 19 (46.3) | 19 (45.2) | 9 (56.3) | 5 (29.4) |
| Skin | 1 (2.4) | 0 | 1 (6.3) | 1 (5.9) |
| Soft tissue | 2 (4.9) | 0 | 0 | 0 |
| Lymph nodes | 23 (56.1) | 18 (42.9) | 8 (50.0) | 4 (23.5) |
| Number of prior antineoplastic regimens, n (%) | ||||
| 1 | 2 (4.9) | 2 (4.8) | 0 | 4 (23.5) |
| 2 | 3 (7.3) | 5 (11.9) | 6 (37.5) | 3 (17.6) |
| 3 | 11 (26.8) | 10 (23.8) | 4 (25.0) | 4 (23.5) |
| 4 | 4 (9.8) | 9 (21.4) | 1 (6.3) | 1 (5.9) |
| 5 | 12 (29.3) | 7 (16.7) | 4 (25.0) | 4 (23.5) |
| >5 | 9 (22.0) | 8 (19.0) | 1 (6.3) | 1 (5.9) |
| Setting at last medication, n (%) | ||||
| Adjuvant | 4 (9.8) | 7 (16.7) | 5 (31.3) | 3 (17.6) |
| Neoadjuvant | 0 | 1 (2.4) | 0 | 1 (5.9) |
| Metastatic | 37 (90.2) | 33 (78.6) | 11 (68.8) | 13 (76.5) |
| Prior therapies received in the advanced/metastatic setting, n (%) | ||||
| Chemotherapy | 20 (48.8) | 20 (47.6) | 4 (25.0) | 2 (11.8) |
| Endocrine therapy | 36 (87.8) | 31 (73.8) | 9 (56.3) | 12 (70.6) |
| Anastrozole | 15 (36.6) | 6 (14.3) | 2 (12.5) | 1 (5.9) |
| Fulvestrant | 25 (61.0) | 16 (38.1) | 2 (12.5) | 3 (17.6) |
| Letrozole | 20 (48.8) | 21 (50.0) | 6 (37.5) | 11 (64.7) |
| Tamoxifen | 8 (19.5) | 6 (14.3) | 1 (6.3) | 1 (5.9) |
| Exemestane | 12 (29.3) | 10 (23.8) | 0 | 0 |
| Other | 9 (22.0) | 9 (21.4) | 3 (18.8) | 1 (5.9) |
| Targeted therapy | 10 (24.4) | 8 (19.0) | 1 (6.3) | 14 (82.4) |
| PI3K/Akt/mTOR inhibitors | 12 (29.3) | 9 (21.4) | 2 (12.5) | 1 (5.9) |
| Other | 6 (14.6) | 3 (7.1) | 1 (6.3) | 0 |
| Patients with measurable disease, n (%) | 35 (85.4) | 34 (81.0) | 12 (75.0) | 14 (82.4) |
Abbreviations: CNS, central nervous system; WHO, World Health Organization.
0 = fully active, able to carry on all predisease performance without restriction; 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.
Dose-escalation phase: group 1 (fasting), 32/41 patients (78.0%); group 2 (fed), 25/42 patients (59.5%)
Dose-expansion phase: group 1 (CDK4/6i-naïve), 11/16 patients (68.8%); group 2 (CDK4/6i-refractory), 12/17 patients (70.6%)
The median age of patients in each cohort is presented in Table 1: the overall median age was 57.4 years (range, 31–84). The majority of patients were white (n = 92; 79%) and approximately half of the patients had an ECOG PS of 0; none of the patients had an ECOG PS >1. Many patients had >1 site of metastasis [≤3 sites, n = 72 (62.1%); >3 sites, n = 44 (38.9%)]. The most common sites of metastasis were bone (92 patients, 79.3%), liver (66 patients, 56.9%), lymph nodes (53 patients, 45.7%), and lung (52 patients, 44.8%).
All patients except one had received prior antineoplastic medication; details of these therapies are presented in Table 1. As of the data cut-off (March 14, 2018), treatment was ongoing in one patient in the dose-escalation group 2 (fed) and in three patients in the dose-expansion phase [group 1 (CDK4/6i-naïve), n = 1; group 2 (CDK4/6i-refractory), n = 2]. In the dose-escalation phase, the median durations of exposure to study treatment were 5.5 months (range, 0.6–36.8 months) and 5.1 months (range, 0.9–38.0 months) in dose-escalation groups 1 (fasting) and 2 (fed), respectively. In the dose-expansion phase, median durations of exposure to study treatment were 9.3 months (range, 0.9–24.6 months) and 1.9 months (range, 1.1–18.4 months) in the CDK4/6i-naïve group and the CDK4/6i-refractory group, respectively.
MTD/RP2D
The dose-escalation phase included 70 evaluable patients treated with triplet therapy. Seven (10%) patients experienced ≥1 event that met the definition of a DLT [group 1 (fasting), n = 4; group 2 (fed), n = 3].
The DLTs reported in dose-escalation group 1 were in two patients who had both increased alanine aminotransferase (ALT; grade 3) and increased aspartate aminotransferase (AST; grade 3), one patient who had hypophosphatemia (grade 3) and febrile neutropenia (grade 3), and one patient who had rash (grade 3) and thrombocytopenia (grade 3). DLTs reported in dose-escalation group 2 were in one patient who had stomatitis (grade 3), one patient who had thrombocytopenia (grade 3), and 1 patient who had hemoptysis (grade 1) and thrombocytopenia (grade 3).
The RP2D for the triplet escalation cohort was determined to be ribociclib 300 mg once daily (3 weeks on/1 week off in a 4-week cycle) plus everolimus 2.5 mg once daily plus exemestane 25 mg once daily taken with food. This dose combination was confirmed to be the RP2D based on the safety and pharmacokinetic data in the triplet escalation fasting and fed cohorts, as well as the recommendation from the BLRM. The MTD was not reached, owing to concerns regarding dose-dependent exponential increases in DDIs between everolimus and ribociclib, which could result in unnecessary toxicity and compromise patient safety.
Safety
AEs
Safety data were examined in the 116 patients treated with triplet therapy in the dose-escalation and dose-expansion phases; of these, 62 patients were included in the RP2D set [i.e., patients treated at the RP2D in the dose-escalation phase (n = 29) and in the dose-expansion phase (n = 33)]. The rates of all-grade, grade 3, and grade 4 treatment-related AEs were 96.6%, 63.8%, and 10.3%, respectively. Overall, the treatment-related AEs of all grades reported in ≥30% of patients in all treatment groups were anemia, stomatitis, neutropenia (and decreased neutrophil count), decreased white blood cell count, increased AST levels, nausea, fatigue, and thrombocytopenia. The most common grade 3/4 AEs observed (≥25% of patients) included anemia, stomatitis, and neutropenia (Table 2). In the dose-escalation phase, SAEs were experienced by 14 (34.1%) and 12 (28.6%) patients in groups 1 (fasting) and 2 (fed), respectively. In the dose-expansion phase, four (25.0%) patients in group 1 (CDK4/6i-naïve) and one (5.9%) patient in group 2 (CDK4/6i-refractory) experienced SAEs. In the dose-escalation groups, on-treatment QT values corrected by Fridericia formula (QTcF) prolongation (>480 ms and >500 ms) occurred in four (4.8%) patients and two (2.4%) patients, respectively. No patients in the dose-expansion phase experienced QTcF prolongation. SAEs suspected to be related to study treatment are summarized in Table 3.
Table 2.
Most common grade 3/4 AEs that occurred in ≥25% of all patients in any of the treatment groups treated with the triple combination.
| Preferred term | Dose-escalation group 1 (fasting) n = 41 |
Dose-escalation group 2 (fed) n = 42 |
Dose-expansion group 1 (CDK4/6i-naïve) n = 16 |
Dose-expansion group 2 (CDK4/6i-refractory) n = 17 |
||||
|---|---|---|---|---|---|---|---|---|
| Grade 3 | Grade 4 | Grade 3 | Grade 4 | Grade 3 | Grade 4 | Grade 3 | Grade 4 | |
| Total, n (%) | 27 (65.9) | 6 (14.6) | 30 (71.4) | 8 (19.0) | 15 (93.8) | 1 (6.3) | 11 (64.7) | 2 (11.8) |
| Anemia | 5 (12.2) | 0 | 6 (14.3) | 0 | 2 (12.5) | 0 | 1 (5.9) | 0 |
| Stomatitis | 2 (4.9) | 0 | 1 (2.4) | 0 | 3 (18.8) | 0 | 0 | 0 |
| Neutropenia | 11 (26.8) | 0 | 11 (26.2) | 4 (9.5) | 6 (37.5) | 1 (6.3) | 5 (29.4) | 1 (5.9) |
| Neutrophil count decreased | 9 (22.0) | 4 (9.8) | 9 (21.4) | 1 (2.4) | 10 (62.5) | 0 | 6 (35.3) | 1 (5.9) |
| White blood cell count decreased | 8 (19.5) | 0 | 11 (26.2) | 0 | 4 (25.0) | 0 | 5 (29.4) | 0 |
Note: A patient with multiple occurrences of an AE under one treatment is counted only once in the AE category for that treatment. A patient with multiple AEs is counted only once in the total row. AEs occurring up to 30 days after the final study treatment administration were included.
Table 3.
SAEs with suspected relationship to study treatment, by preferred term–all grades.
| Preferred term | Dose-escalation group 1 (fasting) n = 41 |
Dose-escalation group 2 (fed) n = 42 |
Dose-expansion group 1 (CDK4/6i-naïve) n = 16 |
Dose-expansion group 2 (CDK4/6i-refractory) n = 17 |
|---|---|---|---|---|
| Total | 6 (14.6) | 4 (9.5) | 2 (12.5) | 0 |
| Pneumonitis | 1 (2.4) | 0 | 2 (12.5) | 0 |
| Pneumonia | 1 (2.4) | 0 | 0 | 0 |
| Anemia | 1 (2.4) | 1 (2.4) | 0 | 0 |
| Abdominal pain | 0 | 1 (2.4) | 0 | 0 |
| Cellulitis | 0 | 1 (2.4) | 0 | 0 |
| Diarrhea | 0 | 1 (2.4) | 0 | 0 |
| Dyspnea | 0 | 1 (2.4) | 0 | 0 |
| Febrile neutropenia | 1 (2.4) | 0 | 0 | 0 |
| Lymphopenia | 1 (2.4) | 0 | 0 | 0 |
| Pneumocystis jirovecii infection | 0 | 0 | 1 (6.3) | 0 |
| Rash | 1 (2.4) | 0 | 0 | 0 |
| Renal failure | 1 (2.4) | 0 | 0 | 0 |
| Thrombocytopenia | 1 (2.4) | 0 | 0 | 0 |
Note: A patient with multiple occurrences of an SAE under one treatment is counted only once in the SAE category for that treatment.
SAEs occurring up to 30 days after the final study treatment administration were included.
Overall, 71 (61.2%) patients experienced an AE requiring a dose interruption and/or dose modification. Reasons for these are presented in Table 4.
Table 4.
Study treatment discontinuations, dose reductions, and interruptions in patients treated with triplet combination.
| Preferred term | Dose-escalation group 1 (fasting) n = 41 |
Dose-escalation group 2 (fed) n = 42 |
Dose-expansion group 1 (CDK4/6i-naïve) n = 16 |
Dose-expansion group 2 (CDK4/6i-refractory) n = 17 |
|---|---|---|---|---|
| Treatment discontinuation by AE | ||||
| Total | 3 (7.3) | 3 (7.1) | 2 (12.5) | 1 (5.9) |
| Pneumonia | 0 | 1 (2.4) | 0 | 0 |
| ALT increased | 0 | 1 (2.4) | 0 | 1 (5.9) |
| Neutropenia | 1 (2.4) | 1 (2.4) | 0 | 0 |
| AST increased | 0 | 0 | 1 (6.3) | 0 |
| GGT increased | 1 (2.4) | 0 | 0 | 0 |
| Infectious colitis | 0 | 1 (2.4) | 0 | 0 |
| Pyrexia | 0 | 0 | 1 (6.3) | 0 |
| Renal failure | 1 (2.4) | 0 | 0 | 0 |
| Thrombocytopenia | 1 (2.4) | 0 | 0 | 0 |
| ≥1 dose reductions by reasona | ||||
| AE | 8 (19.5) | 12 (28.6) | 7 (43.8) | 4 (23.5) |
| Dosing error | 1 (2.4) | 3 (7.1) | 0 | 0 |
| ≥1 dose interruption by reason | ||||
| AE | 17 (41.5) | 20 (47.6) | 13 (81.3) | 7 (41.2) |
| Per protocol | 1 (2.4) | 3 (7.1) | 1 (6.3) | 1 (5.9) |
| Concomitant medication affecting drug exposure | 0 | 3 (7.1) | 0 | 0 |
| Dispensing error | 0 | 1 (2.4) | 0 | 0 |
| Dosing error | 12 (29.3) | 15 (35.7) | 2 (12.5) | 2 (11.8) |
| Scheduling conflict | 18 (43.9) | 16 (38.1) | 7 (43.8) | 9 (52.9) |
Note: A patient with multiple occurrences of an AE under one treatment is counted only once in the AE category for that treatment. AEs occurring up to 30 days after the final study treatment administration were included.
Abbreviation: GGT, gamma-glutamyl transferase.
Dose reduction of exemestane was not permitted in the study.
Dose reductions, interruptions, and discontinuations
Ribociclib:
In dose-escalation group 1 (fasting), nine (22.0%) patients required ≥1 dose reduction and 28 (68.3%) patients required ≥1 dose interruption. In dose-escalation group 2 (fed), 14 (33.3%) patients required ≥1 dose reduction, and 34 (80.9%) patients required ≥1 dose interruption. In dose-expansion group 1 (CDK4/6i-naïve), seven (43.8%) patients required ≥1 dose reduction and 14 (87.5%) patients required ≥1 dose interruption. In dose-expansion group 2 (CDK4/6i-refractory), four (23.5%) patients required ≥1 dose reduction and 14 (82.4%) patients required ≥1 dose interruption.
Everolimus:
In dose-escalation group 1 (fasting), one (2.4%) patient required ≥1 dose reduction (due to AE), and 29 (70.7%) patients required ≥1 dose interruption. In dose-escalation group 2 (fed), two (4.8%) patients required ≥1 dose reduction and 35 (83.3%) patients required ≥1 dose interruption. There were no dose reductions of everolimus in the dose-expansion phase.
Exemestane:
Dose reductions of exemestane were not permitted in the study. In dose-escalation group 1 (fasting), 25 (61%) patients required ≥1 dose interruption. In dose-escalation group 2 (fed), 30 (71.4%) patients required ≥1 dose interruption. In dose-expansion group 1 (CDK4/6i-naïve), 11 (68.8%) patients required ≥1 dose interruption. In dose-expansion group 1 (CDK4/6i-naïve), 7 (43.8%) patients required ≥1 dose interruption. In dose-expansion group 2 (CDK4/6i-refractory), 12 (70.6%) patients required ≥1 dose interruption.
Nine (7.8%) patients discontinued treatment because of an AE (Table 4); the AEs leading to treatment discontinuation were increased ALT (n = 2, grade 4), neutropenia (n = 2, grade 3), pneumonia (n = 1, grade 3), increased AST (n = 1, grade 4), increased γ-glutamyl transferase (n = 1, all-grade), infectious colitis(n = 1, grade 3), pyrexia (n = 1, all-grade), renal failure (n = 1, grade 4), and thrombocytopenia (n = 1, grade 3). There was one on-treatment death in the dose-escalation phase of the study. This patient was hospitalized 25 days after their last dose of the study treatment with sepsis (grade 3), right lower lobe pneumonia (grade 3), and acute respiratory failure (grade 4). Despite treatment that included antibiotics and ventilatory support, the patient died as a result of acute respiratory failure, which was not considered related to study treatment.
Pharmacokinetics
Pharmacokinetic data for maximum drug concentration (Cmax) and area under the plasma concentration-time curve over the last 24-hour dosing interval (AUC0–24h) for ribociclib and everolimus were available on day 1 and after multiple doses on day 15. Ribociclib was rapidly absorbed, with median time to maximum concentration (Tmax) ranging from 1 to 4 hours on cycle 1 day 1. For ribociclib, the geometric mean Cmax at steady state in dose-escalation group 1 (200–350 mg dose) ranged from 413 to 1,000 ng/mL and the geometric mean Cmax in dose-escalation group 2 ranged from 289 to 955 ng/mL; at the RP2D the Cmax at steady state was 773 ng/mL. The corresponding geometric mean AUC0–24h at steady state for ribociclib in dose-escalation group 1 ranged from 4,570 to 11,100 hours* ng/mL, and the geometric mean AUC0–24h in dose-escalation group 2 ranged from 3,970 to 13,400 hours* ng/mL; at RP2D, the AUC0–24 at steady state was 10,200 hours* ng/mL.
The mean steady-state exposure for ribociclib appeared to be slightly lower in the presence of food at the same dose level; however, individual Cmax and AUC0–24h values with food were within the range of values observed without food (Supplementary Table S1; Supplementary Fig. S1). The accumulation ratio across the ribociclib dose levels (200–350 mg) ranged from 2.11 to 3.15 in dose-escalation group 1 and from 1.34 to 3.54 in dose-escalation group 2. In dose-escalation group 1, geometric mean effective half-lives based on drug accumulation (range, 24.9–47.6 hours) were generally similar to those in dose-escalation group 2 (range, 29.5–49.9 hours).
Everolimus was rapidly absorbed, with median Tmax ranging from 1 to 2 hours on cycle 1 day 1. In dose-escalation group 1, the geometric mean Cmax at steady state for everolimus 2.5 mg ranged from 19.7 to 30.3 ng/mL, and in dose-escalation group 2 the geometric mean Cmax ranged from 8.25 to 29.4ng/mL. The corresponding AUC0–24h in dose-escalation group 1 ranged from 166 to 307 hours* ng/mL, and from 117 to 316 hours* ng/mL in dose-escalation group 2; at the RP2D, the Cmax at steady state was 25.1 ng/mL and AUC0–24h was 303 hours* ng/mL. Further details of these pharmacokinetic data are available in the Supplementary Appendix (Supplementary Tables S1 and S2; Supplementary Figs. S1 and S2).
Exemestane concentrations in the triplet combination with ribociclib (dose range, 200–350 mg) and everolimus (dose range, 1–5 mg) at 2 hours (around Tmax) on cycle 1 day 1 and at 2 hours on cycle 1 day 15 were comparable with the historical data of single-agent exemestane (25).
No DDIs were observed for ribociclib in the presence of everolimus and exemestane in the triplet combination, as demonstrated by exposure data that were within the range observed for single-agent ribociclib (26). A dose-dependent DDI was observed for everolimus, with everolimus exposure increasing two- to fourfold in the presence of ribociclib in the dose-escalation phase (Supplementary Fig. S2). The increased exposure of everolimus 2.5–5 mg/day in the presence of ribociclib 200–350 mg/day was similar to historical data for single-agent everolimus at a dose of 5–10 mg. Comparing exemestane concentrations with historical data indicated no DDI with ribociclib or everolimus (phase I study CRAD001C2101/02).
A dose-dependent DDI was observed for everolimus, with everolimus exposure increasing two- to fourfold in the presence of ribociclib in the dose-escalation phase (Supplementary Fig. S2), but exposures of exemestane or ribociclib were not impacted by everolimus.
Efficacy and biomarkers
ORRs and CBRs were examined in the patients with measurable disease who were treated with triplet therapy in the dose-escalation and dose-expansion phases [95/116 (81.9%)]. In the dose-escalation phase, ORR was 11.4% for patients in group 1 (fasting) and 14.7% for patients in group 2 (fed), as outlined in the waterfall plot in Supplementary Fig. S3. No patient in the dose-expansion phase achieved a PR or CR. In the dose-escalation phase, CBRs were 40.0% [95% confidence interval (CI), 23.9–57.9] in group 1 (fasting) and 47.1% (95% CI, 29.8–64.9) in group 2 (fed); in the dose-expansion phase, CBRs were 50.0% (95% CI, 21.1–78.9) in group 1 (CDK4/6i-naïve) and 14.3% (95% CI, 1.8–42.8) in group 2 (CDK4/6i-refractory). Caution should be exercised in interpreting CBRs in uncontrolled studies. PFS was assessed for patients with both measurable and nonmeasurable disease, and was 5.6 months (95% CI, 3.7–9.6) and 8.4 months (95% CI, 3.9–13.0) in dose-escalation groups 1 (fasting) and 2 (fed), respectively, and 12.7 months (95% CI, 3.7–20.2) and 1.9 months (95% CI, 1.7–7.3) in dose-expansion groups 1 (CDK4/6i-naïve) and 2 (CDK4/6i-refractory), respectively (Supplementary Fig. S3).
Tumor shrinkage, defined as change from baseline (best percentage) in sum of longest diameters, was experienced by 20/32 (62.5%) patients in dose-escalation group 1 (fasting), 17/33 (51.5%) patients in dose-escalation group 2 (fed), 6/10 (60.0%) patients in dose-expansion group 1 (CDK4/6i-naïve), and 1/14 (7.1%) patients in dose-expansion group 2 (CDK4/6i-refractory; Supplementary Fig. S4).
In the dose-expansion phase, tumor biopsies allowing for the analysis of baseline gene expression patterns were available in 14/33 patients treated with triplet therapy (27). In an exploratory analysis, both dose expansion groups demonstrated a trend toward higher overall baseline expression of cell-cycle control genes and genes involved in the MAPK pathway in patients with PD compared with those with SD. In dose-expansion group 2 (CDK4/6i-refractory), a trend for higher baseline CDK2 and/or CCNE1 expression was evident in patients with PD in comparison with patients with SD (Fig. 2). Across both dose-expansion groups, patients with SD had higher median ESR1 expression than those with PD (Fig. 2). There was also a trend for higher baseline ESR1 expression in dose expansion group 1 (CDK4/6i-naïve) compared with group 2 (CDK4/6i-refractory; Fig. 2).
Figure 2.
Baseline gene expression by NanoString with best overall response in CDK4/6i–naïve and -refractory patients. A, Cell-cycle control gene expression with best overall response in CDK4/6i–naïve and –refractory patients; B, MAPK pathway gene expression with best overall response in CDK4/6i–naïve and –refractory patients; C, CCNE1 expression with best overall response in CDK4/6i–naïve and –refractory patients; D, CDK2 expression with best overall response in CDK4/6i–naïve and –refractory patients; E, ESR1 expression with best overall response in CDK4/6i–naïve and –refractory patients. Data points sitting either side of the PD or SD data line are for esthetic purposes only. aCell-cycle control genes include CCNA2, CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, RB1, E2F1, E2F3, TFDP1, and TP53. CCNE1, cyclin E1 gene; ESR1, estrogen receptor 1; mRNA, messenger ribonucleic acid.
Across all patients in the dose-expansion phase, a higher numerical trend was present for ESR1 gene expression and a better response to triplet therapy; conversely, a higher gene expression of cell-cycle control genes and/or MAPK pathway genes appeared to trend with a worse treatment response (Fig. 2). No formal statistical analyses were performed because of small sample sizes.
Discussion
The safety profile of triplet therapy of ribociclib plus everolimus plus exemestane is consistent with the known profiles of the combination partners, and the triplet therapy was generally well tolerated. AEs were manageable with dose modifications and concomitant medications and no new or unexpected safety signals were identified. The incidence and severity of hematologic AEs (which are commonly observed with CDK4/6is) were similar to those seen with ribociclib combinations with ET alone in the phase III setting (28–30). The incidences of all-grade stomatitis were within the ranges observed in the BOLERO studies of everolimus and exemestane in patients with HR+, HER2− ABC (5, 13). Although patient numbers were limited, tolerability of the combination appeared to be better in the fed versus fasted state; this was demonstrated by a low incidence of all AEs of special interest, including increased liver function test results observed relative to the ribociclib plus letrozole treatment seen in the MONALEESA trial program (28).
In the dose-escalation phase, the RP2D was determined, based on the safety and pharmacokinetic data observed in this study, as ribociclib 300 mg once daily (3 weeks on/1 week off) in combination with everolimus 2.5 mg once daily (continuous) and exemestane 25 mg once daily (continuous), to be taken with food. Pharmacokinetic parameters for ribociclib in the fed state remained within the range observed in the fasted state, confirming a minimal food effect. A dose-dependent DDI was observed for everolimus, with an increased exposure of everolimus 2.5–5 mg/day in the presence of ribociclib 200–350 mg/day; these data are similar to historical data for single-agent everolimus at a dose of 5–10 mg (CRAD001C2101/02). Ribociclib in combination with everolimus and exemestane is therefore recommended to be taken with food in future studies, because exemestane and everolimus are generally given with food and a DDI was observed for everolimus in the presence of ribociclib.
Preliminary evidence of antitumor activity with the triplet combination was observed, as demonstrated by efficacy results for ORR and CBR. The CBRs for patients with measurable disease in the dose-escalation phase were 40.0% in group 1 (fasting) and 47.1% in group 2 (fed); in the dose expansion phase, the CBRs were 50.0% in group 1 (CDK4/6i-naïve) and 14.3% in group 2 (CDK4/6i-refractory). In comparison, in the phase Ib/II trial TRINITI-1 (ClinicalTrials.gov number, NCT02732119), CBR was 41.1% in patients treated with a continuous triplet combination of ribociclib (200 or 300 mg) with everolimus (2.5 or 5 mg) plus exemestane (25 mg; ref. 31). Antitumor activity had previously been demonstrated in the phase III trial, BOLERO-2, where there was a CBR of 79.6% in patients treated with everolimus plus exemestane (5).
The median PFS of 12.7 months achieved in dose expansion group 1 (CDK4/6i-naïve, n = 16) is in line with results seen in other trials studying second-line ET for ABC, such as patients treated in the second-line in MONALEESA-3, a study of ribociclib plus fulvestrant (14.6 months, n = 237; ref. 11), and SOLAR-1, which explored alpelisib plus fulvestrant in patients with a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation (11.0 months, n = 169; ref. 4). Although 25% (n = 4) of patients in dose-expansion group 1 received prior chemotherapy for advanced disease, the MONALEESA-3 and SOLAR-1 studies did not allow patients with prior chemotherapy for advanced disease. Therefore, while this comparison with other trials is made with caution, these results, in addition to preclinical evidence, suggest that the further investigation of CDK4/6 blockade and cotargeting of the PI3K/mTOR signaling pathway is worthy of further exploration in pretreated patient populations (17, 32, 33).
Differences in baseline gene expression and treatment response were observed in CDK4/6i-naïve and CDK4/6i-refractory patients treated with triplet therapy in the dose-expansion phase. In dose-expansion group 2 (CDK4/6i-refractory), though sample size is very small, a trend for higher baseline CDK2 and/or CCNE1 expression was observed in patients with PD compared with patients with SD. It is worth noting that a published preclinical finding showed that CDK2 activation or CCNE1 amplification may be a mechanism of resistance to CDK4/6 inhibition with palbociclib (18). In addition, it was shown in PALOMA-3 that a high expression of CCNE1 was significantly associated with poor outcomes in patients treated with palbociclib in combination with fulvestrant (34); however, in MONALEESA-3, ribociclib demonstrated similar PFS benefit regardless of the gene expression levels of CCNE1 (35). These results warrant further investigation of the role that CCNE1 may play in the resistance to CDK4/6 inhibition in the clinical setting.
In this study, a higher gene expression of cell-cycle control genes and/or MAPK pathway genes appeared to trend with a worse treatment response. In addition, there was a trend for higher baseline ESR1 expression in dose-expansion group 1 (CDK4/6i-naïve) compared with group 2 (CDK4/6i-refractory). Although the biomarker analysis was restricted to a small sample size in dose expansion, which limits interpretation of the results, further investigation of gene expression patterns and other biomarkers in correlation with treatment response is warranted. TRINITI-1 (NCT02732119) showed that certain tumor alterations such as ESR1 had shorter median PFS [HR 1.76 (95% CI, 0.01–3.05)]. Tumor genetic profiling may contribute to the identification of patient populations that would derive clinical benefit from this triplet therapy.
These data provide evidence that the triplet combination of ribociclib with everolimus and exemestane provides a clinical benefit with an acceptable safety profile in postmenopausal women with HR+, HER2− ABC who could have received several prior lines of treatment. Further biomarker investigation in a much larger cohort is warranted to identify patients that could benefit most from this triplet therapy.
Supplementary Material
Translational Relevance.
Endocrine therapy plus CDK4/6 inhibitors has become a preferred treatment option forHR+, HER2− ABC; however, endocrine resistance often develops, and a patient’s disease is rarely resolved. Preclinical and clinical data suggest that inhibiting CDK4/6 activity or the PI3K signaling pathway may delay the development of endocrine resistance. This hypothesis has been tested in this dose-escalation/expansion phase Ib trial of triplet therapy with ribociclib, everolimus, and exemestane. The data presented here show that this triplet therapy has a safety profile consistent with the known profiles of the combination partners and was generally well tolerated. Adverse events were manageable with dose modifications; no new or unexpected safety signals were identified. Preliminary evidence of antitumor activity of the triplet combination was observed, as demonstrated by efficacy results for overall response and clinical benefit. In the CDK4/6 inhibitor–naïve and CDK4/6 inhibitor–refractory patients, differences in baseline gene expression and in treatment response were observed.
Acknowledgments
This work was supported by Novartis Pharmaceuticals, which also funded medical writing assistance.
We thank the patients who took part in this trial and their families, as well as staff members at each study site. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Lauren Halliwell, Healthcare Consultancy Group LLC, for her medical editorial assistance with this manuscript.
Footnotes
Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
Clinicaltrials.gov Identifier: NCT01857193.
Disclosure of Potential Conflicts of Interest
A. Bardia reports grants and personal fees from Novartis (research grant to institution; personal fees as consultant) during the conduct of the study; personal fees from Genentech, Merck, Radius Health, Immunomedics, Taiho, Sanofi, Diiachi Pharma/Astra Zeneca, Puma, Biothernostics Inc., Phillips, Eli Lilly, Foundation Medicine (consultant) and grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics, Diiachi Pharma/Astra Zeneca. (contracted research/grant to institution) outside the submitted work. S. Modi reports personal fees from Genentech (advisory, consulting and speaking honoraria), Daiichi Sankyo (advisory, consulting and speaking honoraria), Seattle Genetics (advisory, consulting and speaking honoraria), AstraZeneca (advisory, consulting and speaking honoraria), Macrogenics (advisory, consulting), and Novartis (consulting) outside the submitted work. M. Oliveira reports grants from Novartis (to the institution) during the conduct of the study; personal fees and nonfinancial support from Novartis; grants, personal fees, and nonfinancial support from Roche; grants and personal fees from Seattle Genetics, AstraZeneca, PUMA Biotechnology, Genentech; grants from Immunomedics, Boehringer-Ingelheim; nonfinancial support from Pierre-Fabre, Eisai, GP Pharma, and Grunenthal outside the submitted work. J. Cortes reports€ personal fees from Novartis (honoraria) during the conduct of the study; personal fees from Roche (advisor/honoraria), Celgene (advisor/honoraria), AstraZeneca (advisor), Cellestia (advisor), Biothera (advisor), Merus (advisor), Seattle Genetics (advisor), Daiichi Sankyo (advisor/honoraria), Erytech (advisor), Athenex (advisor), Polyphor (advisor), Lilly (advisor/honoraria), Servier (advisor), Merck Sharp & Dhome (advisor/honoraria), GSK (advisor), Leuko (advisor), Bioasis (advisor), Clovis Oncology (advisor), Boehringer (advisor), Novartis (honoraria), EISAI (honoraria), Pfizer (honoraria), Samsung Bioepis (honoraria), and MedSIR (stock) outside the submitted work. M. Campone reports personal fees from Novartis (speaker bureau) during the conduct of the study; other from AstraZeneca (fee to the institution-advisory board), Novartis (fee to the institution-advisory board), Abbvie (fee to the institution-advisory board), Sanofi (fee to the institution-consultant-advisory board), Pfizer (fee to the institution-advisory board), Pierre Fabre (fee to the institution-consultant), Servier (fee to the institution-consultant), and personal fees from Lilly (advisory board) and GT1 (consultant) outside the submitted work. B. Ma reports grants and other from Novartis (advisory board) outside the submitted work. B. Hewes reports other from Novartis (employee) during the conduct of the study. I. Diaz-Padilla reports other from Novartis (employee) outside the submitted work. Y. Han reports other from Healthcare Consultancy Group LLC (manuscript preparation) during the conduct of the study; other from Novartis (employed by Novartis) outside the submitted work. T.S. Samant reports other from Novartis Pharmaceuticals (employee of Novartis) outside the submitted work. K. Rodriguez Lorenc reports other from Novartis Pharmaceuticals and Regeneron Pharmaceuticals outside the submitted work. F. Su reports other from Novartis Pharmaceuticals (employee and stock holder) during the conduct of the study; in addition, F. Su has a patent for PAT057844-WO-PCT pending. M. Chavez-MacGregor reports grants from Novartis (institutional support) during the conduct of the study; other from Novartis (advisory board), Roche (advisory board), AstraZeneca (advisory board), and Pfizer (advisory board) outside the submitted work. No potential conflicts of interest were disclosed by the other authors.
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