Friedrich Graf Finckenstein

Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC).

LBA109 Background: Options for advanced non-SQ NSCLC patients (pts) who progress after platinum-based doublet chemotherapy (PT-DC) are limited, with minimal improvement in overall survival (OS). We report results from a randomized, global phase III study of NIVO, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, vs DOC in pts with advanced non-SQ NSCLC after failure of PT-DC and tyrosine kinase inhibitor, if eligible. METHODS Pts were randomized to NIVO 3 mg/kg Q2W (n=292) or DOC 75 mg/m2 Q3W (n=290) until progression or discontinuation due to toxicity/other reasons. Primary objective was OS; Secondary objectives were investigator-assessed objective response rate (ORR; per RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 expression, quality of life, and safety. RESULTS NIVO demonstrated superior OS (HR=0.73; 96% CI: 0.59, 0.89; P=0.00155) and improved ORR (19.2% vs 12.4%; P=0.0235). HR for PFS was 0.92 (95% CI: 0.77, 1.11; P=0.393). PD-L1 expression was associated with benefit from NIVO (Table). In PD-L1+ pts, NIVO showed improved efficacy across all endpoints at predefined 1%, 5%, and 10% cut- points. Grade 3-5 drug-related AEs occurred in 10.5% (30/287) of NIVO and 53.7% (144/268) of DOC pts. No deaths were related to NIVO vs 1 DOC-related death. After discontinuation, 42.1% of NIVO and 49.7% of DOC pts received subsequent systemic therapy. CONCLUSIONS NIVO demonstrated superior OS vs DOC in pts with advanced non-SQ NSCLC after failure of PT-DC. The safety profile of NIVO 3 mg/kg Q2W was favorable vs DOC. NIVO demonstrated survival benefit across histologies in two randomized phase III trials. CLINICAL TRIAL INFORMATION NCT01673867. [Table: see text].

Dual IGF-1R/InsR Inhibitor BMS-754807 Synergizes with Hormonal Agents in Treatment of Estrogen-Dependent Breast Cancer

Insulin-like growth factor (IGF) signaling has been implicated in the resistance to hormonal therapy in breast cancer. Using a model of postmenopausal, estrogen-dependent breast cancer, we investigated the antitumor effects of the dual IGF-1R/InsR tyrosine kinase inhibitor BMS-754807 alone and in combination with letrozole or tamoxifen. BMS-754807 exhibited antiproliferative effects in vitro that synergized strongly in combination with letrozole or 4-hydroxytamoxifen and fulvestrant. Similarly, combined treatment of BMS-754807 with either tamoxifen or letrozole in vivo elicited tumor regressions not achieved by single-agent therapy. Notably, hormonal therapy enhanced the inhibition of IGF-1R/InsR without major side effects in animals. Microarray expression analysis revealed downregulation of cell-cycle control and survival pathways and upregulation of erbB in response to BMS-754807 plus hormonal therapy, particularly tamoxifen. Overall, these results offer a preclinical proof-of-concept for BMS-754807 as an antitumor agent in combination with hormonal therapies in hormone-sensitive breast cancer. Cooperative cell-cycle arrest, decreased proliferation, and enhanced promotion of apoptosis may contribute to antitumor effects to be gauged in future clinical investigations justified by our findings.

Dual Inhibition of the Epidermal Growth Factor Receptor Pathway with Cetuximab and Erlotinib: A Phase I Study in Patients with Advanced Solid Malignancies

PURPOSE To determine the optimal dose of the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab that can be safely administered in combination with a standard daily dose of erlotinib in patients with advanced solid malignancies. PATIENTS AND METHODS Patients with advanced solid malignancies who had failed standard chemotherapies received escalating doses of cetuximab without a loading dose (100, 200, 250 mg/m(2) i.v. weekly) in combination with a fixed dose of erlotinib (150 mg daily orally) until disease progression or unacceptable toxicity. RESULTS Twenty-two patients were treated, including 14 patients (64%) with non-small cell lung cancer. Twenty patients received combination treatment at the highest dose level for a median of 5.5 weeks (range, 1-31 weeks). One dose-limiting toxicity was observed: grade 3 skin rash. Overall, the most common adverse events (any grade, grade 3/4) were consistent with the safety profiles of the individual drugs: acneform rash (100%, 9%), diarrhea (77%, 5%), and hypomagnesemia (59%, 12%). Seven of 18 evaluable patients (38.9%) had stable disease lasting for a median of 16.6 weeks (range, 6.1-25.1 weeks). CONCLUSION Dual EGFR inhibition with cetuximab and erlotinib is feasible; the observed toxicities were manageable and consistent with the safety profiles of the individual drugs. The recommended doses for phase II studies are 250 mg/m(2) i.v. weekly for cetuximab and 150 mg daily orally for erlotinib.

IRS2 Copy Number Gain, KRAS and BRAF Mutation Status as Predictive Biomarkers for Response to the IGF-1R/IR Inhibitor BMS-754807 in Colorectal Cancer Cell Lines

Insulin-like growth factor receptor 1 (IGF-1R)–targeting therapies are currently at an important crossroad given the low clinical response rates seen in unselected patients. Predictive biomarkers for patient selection are critical for improving clinical benefit. Coupling in vitro sensitivity testing of BMS-754807, a dual IGF-1R/IR inhibitor, with genomic interrogations in 60 human colorectal cancer cell lines, we identified biomarkers correlated with response to BMS-754807. The results showed that cell lines with BRAFV600E or KRASG13D mutation were resistant, whereas cell lines with wild-type of both KRAS and BRAF were particularly sensitive to BMS-754807 if they have either higher RNA expression levels of IR-A or lower levels of IGFBP6. In addition, the cell lines with KRAS mutations, those with either insulin receptor substrate 2 (IRS2) copy number gain (CNG) or higher IGF-1R expression levels, were more sensitive to the drug. Furthermore, cell lines with IRS2 CNG had higher levels of ligand-stimulated activation of IGF-1R and AKT, suggesting that these cell lines with IGF-IR signaling pathways more actively coupled to AKT signaling are more responsive to IGF-1R/IR inhibition. IRS2 siRNA knockdown reduced IRS2 protein expression levels and decreased sensitivity to BMS-754807, providing evidence for the functional involvement of IRS2 in mediating the drug response. The prevalence of IRS2 CNG in colorectal cancer tumors as measured by qPCR-CNV is approximately 35%. In summary, we identified IRS2 CNG, IGF-1R, IR-A, and IGFBP6 RNA expression levels, and KRAS and BRAF mutational status as candidate predictive biomarkers for response to BMS-754807. This work proposed clinical development opportunities for BMS-754807 in colorectal cancer with patient selection to improve clinical benefit. Mol Cancer Ther; 14(2); 620–30. ©2014 AACR.

Nivolumab Exposure–Response Analyses of Efficacy and Safety in Previously Treated Squamous or Nonsquamous Non–Small Cell Lung Cancer

Purpose: Nivolumab is a fully human IgG4 monoclonal antiprogrammed death-1 antibody with demonstrated efficacy, including durable responses and prolonged survival, in patients with previously treated, advanced non–small cell lung cancer (NSCLC). Exposure–response (E–R) analyses for efficacy and safety were conducted to inform the benefit–risk assessment of nivolumab in this patient population. Experimental Design: The analyses used clinical trial data from patients with squamous (n = 293) or nonsquamous (n = 354) NSCLC from four clinical trials who received nivolumab doses of 1 to 10 mg/kg every 2 weeks. E–R efficacy analyses were performed by investigating the relationship between time-averaged nivolumab concentration after the first dose (Cavg1) and the probability of overall survival by histology. E–R safety analyses examined relationships between nivolumab Cavg1 and hazards of adverse events leading to discontinuation or death (AEs-DC/D). Results: Nivolumab exposure was not associated with overall survival [the 95% confidence interval (CI) of effect included 1] in patients with squamous (HR, 0.802; 95% CI, 0.555–1.16) or nonsquamous NSCLC (HR, 0.94; 95% CI, 0.683–1.29). Similarly, nivolumab exposure was not associated with AEs-DC/D in the overall population (HR, 0.917; 95% CI, 0.644–1.31). The risk of AEs-DC/D was similar among patients with squamous or nonsquamous histology. Conclusions: Nivolumab monotherapy demonstrated a wide therapeutic margin, as evidenced by relatively flat E–R relationships over the range of exposures produced by doses of 1 to 10 mg/kg every 2 weeks (Q2W), supporting the use of the initially approved dose of 3 mg/kg Q2W in patients with NSCLC. Clin Cancer Res; 23(18); 5394–405. ©2017 AACR.

Abstract A101: BMS‐754807, an oral dual IGF‐1R/IR inhibitor: First‐in‐human single‐dose study of safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy subjects

Background: Type 1 insulin‐like growth factor receptor (IGF‐1R) signaling drives survival and proliferation in a broad range of human tumors. Insulin receptor (IR) signaling can drive tumor growth and may act as an escape mechanism for IGF‐1R inhibition. BMS‐754807 is a potent and selective reversible inhibitor of IGF‐1R/IR family kinases (IGF‐1R, IR; Ki Methods:CA191001 was a placebo‐controlled, ascending single‐dose study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of BMS‐754807 in healthy subjects. Eight subjects per dose panel were randomized in a 3:1 ratio to receive a single oral dose of BMS‐754807 (2, 10, 20, 30, or 60 mg) or placebo after a 10 h fast. A 75 g glucose challenge was administered 2 h post‐dose at the 10 and 30 mg doses; a second 30 mg panel was dosed without a glucose challenge. The 60 mg panel received a second dose of BMS‐754807 or placebo with a high‐fat meal after at least a 7 day washout. Results: Forty‐eight male subjects received BMS‐754807 (n = 36) or placebo (n = 12). Adverse events (AEs) occurred in 26 subjects, all were mild or moderate. The most frequent AE was hypoglycemia, which occurred in 10 drug‐treated subjects and 1 placebo‐treated subject. Most hypoglycemia AEs occurred in subjects who received a glucose challenge and occurred in these subjects with a higher frequency after the 30 mg dose than after the 10 mg dose. There was no other apparent relationship of AEs, vital signs, or clinical lab abnormalities with dose. BMS‐754807 exposure was proportional to dose; mean half‐life was 9 – 13 h and median Tmax was 1 – 2 h. AUC was similar when administered in the fasted and fed states, however, Cmax was lower and delayed in the fed state. All subjects receiving at least a 10 mg dose exceeded the minimal efficacious exposure predicted from mouse IGF‐1R dependent xenograft tumors (RH41, IGF‐Sal). Dose‐related increases of insulin, C‐peptide and glucose occurred in the fasted state. In dose panels without glucose challenge plasma glucose levels returned to baseline within 4 h post‐dose. In subjects receiving a glucose challenge 2 h post‐dose a second increase of glucose and a marked increase of insulin and C‐peptide was observed, possibly explaining the observed hypoglycemia AEs in these subjects. There was no prolonged elevation of glucose after the glucose challenge. Conclusion: Current data suggest doses of BMS‐754807 in humans that produce exposure predicted to be efficacious are safe and tolerable. Pharmacodynamic effects on insulin and glucose support pharmacologic activity. Dual inhibition of IGF‐1R and IR is feasible and may provide differential activity from IGF‐1R‐specific monoclonal antibodies. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A101.

Abstract 363: Therapeutic targeting of insulin receptor-A with a dual IGF-1R/IR inhibitor: Overcoming a potential escape mechanism from IGF-1R-specific signaling inhibition in insulin receptor-A transfected cancer cells

Type I Insulin-like Growth Factor Receptor (IGF-1R) is a tyrosine kinase receptor that is activated by binding to IGF-1 and IGF-II ligands; IGF-1R has been shown to play a role in cancer development and progression and therapies targeting IGF-1R have resulted in clinical benefit in cancer patients. Insulin Receptor (IR) which is closely related to IGF-1R, is expressed in normal tissues and tumors, and is expressed as two isoforms, IR-A and IR-B. IR-A exhibits mitogenic activity and is preferentially found in fetal tissue and cancer cells, whereas IR-B regulates glucose metabolism in response to insulin. Both IR isoforms bind insulin, and IR-A also binds IGF-II. Several cancer cell types that express IR-A also overexpress IGF-II, suggesting a possible autocrine loop that enhances tumor survival. Since IGF-1R antibodies bind specifically to IGF-1R and not to IR, IR signaling could represent a potential escape mechanism to antibody treatment through the IR-A pathway. BMS-754807, a small molecule inhibitor with dual activity against IGF-1R and IR, recently entered clinical development. It is anticipated that BMS-754807 can prevent or overcome therapeutic resistance resulting from increased IR-activated signaling. The goal of the presented studies was to demonstrate whether dual IGF-1R/IR inhibition by BMS-754807 may prevent IR-mediated resistance to IGF-1R inhibition. To test this hypothesis, a human rhabdomyosarcoma cell line, Rh41 expressing IGF-1R, but little IR, was engineered to express either IR-A (Rh41-IR-A) or IR-B (Rh41-IR-B). IR expression was confirmed by PCR analysis of specific IR isoforms. Rh41-IR-A cells showed phosphorylation of IR after stimulation with IGF-II and/or insulin. MAB391, a neutralizing monoclonal antibody to IGF-1R, inhibited the proliferation of parental Rh41 and Rh41-IR-B cells in vitro, but Rh41-IR-A cells exhibited no sensitivity to the IGF-1R mAb. Combination treatment with both IGF-1R and IR antibodies in Rh41-IR-A cells were strongly synergistic, suggesting dual receptor blocking is required for enhanced anti-tumor efficacy. Inhibition of IGF-1R and IR with BMS-754807 showed the same inhibitory activity in Rh41-IR-A cells as was observed in the parental Rh41 cells. Therefore, dual IGF-1R/IR inhibition by BMS-754807 treatment may overcome the ability of cancer cells to utilize the IR-A pathway and provide an advantage over IGF-1R specific antibodies in the treatment of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 363.

Abstract A153: Mechanisms of acquired resistance to an IGF‐1R inhibitor in multiple models

Background: The IGF‐1R pathway plays a major role in cancer cell proliferation, survival and resistance to anti‐cancer therapies in many human malignancies. Targeting IGF‐1R represents a promising strategy in the development of novel anti‐cancer therapeutics. BMS‐754807, a small molecule inhibitor targeting both IGF‐1R/IR, demonstrated anti‐tumor activity pre‐clinically in multiple tumor types, and is currently in clinical development. A general concern in the clinic with antitumor agents is the development of resistance. In light of this problem, we have developed and characterized cell line models with acquired resistance to BMS‐754807, and identified potential mechanisms and biomarkers for the resistance. Methods: Five cell lines of different tumor types, MCF7, Rh41, Rh1, Geo and SW480 (breast, sarcomas and colon), were induced to develop acquired resistance to BMS‐754807 (range from 5‐ to 38‐fold increased resistance) by stepwise exposure to increasing concentrations of the drug for extended periods. Analyses of in vitro and in vivo drug response, gene expression profiles, signaling pathways and gene copy numbers were performed to characterize the resistant models and the corresponding sensitive parental cells. Results: Cell line specific as well as shared molecular alterations were observed in the different resistant cells using genomic approaches to define mechanisms of resistance to BMS‐754807. The resistant models were also tested against multiple IGF‐1R inhibitors and showed cross‐resistance suggesting common mechanisms of resistance to IGF‐1R inhibition. This presentation will focus on results from the MCF7‐807R model. MCF‐807R cells showed a 5‐fold decrease in IGF‐1R and > 200‐fold increase in IGFBP3 RNA expression levels, as well as overexpression of other growth receptors, such as EGFR, with > 70‐fold increase in both protein and RNA levels compared to the sensitive parental cells. MCF7‐807R and the parental MCF7 cells had differential response to inhibitors of IGF1‐R and EGFR by preferential inhibition of pAKT and pERK. When tested in vitro, MCF7‐807R cells became more sensitive than the parental to multiple EGFR inhibitors presumably due to overexpression of EGFR and growth‐dependence on EGFR; an in vivo xenograft study showed dose‐dependent tumor growth inhibition with cetuximab treatment, whereas the growth of MCF7 parental tumor xenografts was not inhibited by cetuximab. Conclusion: EGFR plays a critical role in resistance to IGF‐1R inhibition; resistant cells and tumors utilized the EGFR pathway to escape growth inhibition. Crosstalk between IGF‐1R and EGFR can confer acquired resistance to IGF‐1R inhibition through compensatory mechanisms by the enhanced activity of the reciprocal EGFR pathway. Dual EGFR and IGFR inhibition may prevent or reverse resistance to IGFR inhibitors offering a promising strategy for exploration in clinical studies to yield greater anticancer activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A153.

Abstract A109: BMS‐754807, an oral, dual IGF‐1R / insulin receptor (IR) inhibitor: Early pharmacodynamic (PD) and positron emission tomography (PET) imaging results from a daily‐dose study in cancer subjects

Background: Inhibiting both IGF‐1R and IR signaling may be required to disrupt the malignant phenotype regulated by the receptor family. BMS‐754807 is a potent and selective reversible inhibitor of IGF‐1R/IR family kinases (IGF‐1R, IR; Ki Methods:CA191002 is an ascending multiple‐dose study to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of BMS‐754807 in subjects with solid tumors. Dosing occurs daily 2 hours after a light breakfast and is followed by a 4 hour fast. PD effects on IR are studied by assessments of plasma glucose, insulin and C‐peptide. 2‐deoxy‐2‐[18F] fluoro‐D‐glucose (FDG)‐ and 3′‐deoxy‐3′‐[18F] fluorothymidine (FLT)‐PET imaging is performed both as imaging markers for PD and to assess anti‐tumor activity. Results: Sixteen subjects have been treated at daily doses of 4, 10, 20, 30 or 50 mg. No dose limiting toxicities have been observed and dose escalation is ongoing. Duration of dosing was between 8 and 197 days. Preliminary analysis shows dose related increases of plasma glucose, insulin and C‐peptide at 2 hours post‐dose (Table 1). The range [median] of plasma glucose at all time points was 68 –187 [95], 50 – 168 [103] and 54 –333 [124] mg/dL in subjects treated at the 4, 10 and 20, and 30 and 50 mg dose levels, respectively. 65 PET scans have been collected from 14 subjects. Preliminary analysis shows that 1 subject with osteosarcoma and 1 subject with adenoid cystic carcinoma achieved 57 and 28 % reduction of tracer uptake, respectively, on FLT‐PET by D12. Both had stable metabolic disease on FDG‐PET by D12 and D56. Conclusion: PD effects of IR inhibition differentiate BMS‐754807 from IGF‐1R specific agents. PET results suggest anti‐tumor activity. Future analysis of PD effects, PET imaging data, safety information and response assessments will provide the basis for a rational selection of subjects and a dose or dose range to be further explored. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A109.