figitumumab (CP-751,871) / Pfizer, Novartis - LARVOL DELTA

Case Report: Should IGF-1R targeted therapy be revisited in Ewing sarcoma? a report of long-term complete response and review of the literature. (PubMed, Front Oncol) - P1, P1/2 | "We present the case of a 42-year-old female with recurrent ES with pulmonary metastases who, after progressing on anti-IGF-1R monotherapy with figitumumab (CP-751,871, NCT00560235), achieved complete remission in a phase I clinical trial (NCT00976508) that combined figitumumab IGF-1R-inhibition with growth hormone receptor antagonist pegvisomant. The impressive response observed highlights the clinical synergy of this combination which warrants further clinical exploration as well as the potential of IGF-1R inhibition for ES. Additionally, this case suggests that targeted therapy discontinuation might be an option for select patients with long-term complete remission."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • IGF1

Diagnostics and Treatment of Extrameningeal Solitary Fibrous Tumors. (PubMed, Cancers (Basel)) - "Other drugs, such as imatinib, figitumumab, axitinib, and eribulin, are also being tested. Definitive radiotherapy appears to be a promising therapeutic modality. Since standards for the treatment of advanced and metastatic diseases are not available, further investigation of novel agents is necessary."

IO biomarker • Journal • Review • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • BCL2 • CD34 • CD99 • NAB2 • STAT6 • VIM

DEVELOPING NOVEL OLIGONUCLEOTIDE THERAPIES TO MODULATE INSULIN RECEPTOR ALTERNATIVE SPLICING IN PEDIATRIC BONE SARCOMAS (CTOS 2023) - "Initial anti-IGF-IR therapies like figitumumab were unsuccessful in a majority of patients in part due to the IR, which can bind the same ligands as IGF-IR and potentiate downstream signaling despite IGF-IR inhibition... Here, we confirm that OS and ES cells and PDXs preferentially express IR-A and that we can therapeutically modulate IR alternative splicing with our SSO in a dose-dependent manner. Additionally, our preliminary results indicate that AAVs, an FDA-approved methodology to deliver SSOs in a tissue-specific manner in pediatric diseases, are a promising approach for pediatric sarcomas as well. Targeting IR alternative splicing with splice-switching therapies and AAV delivery has the potential to address a key resistance mechanism that rendered previously developed anti-IGF-IR therapies ineffective in pediatric sarcoma patients."

Clinical • Ewing Sarcoma • Oncology • Osteosarcoma • Rhabdomyosarcoma • Sarcoma • Solid Tumor • IGF1 • IR

The Immunotherapy Landscape in Adrenocortical Cancer. (PubMed, Cancers (Basel)) - "Immunotherapies that have been evaluated in clinical trials for ACC include the immune checkpoint inhibitors pembrolizumab, nivolumab, and avelumab. Other immunotherapies that have been evaluated include the monoclonal antibodies figitumumab and cixutumumab directed against the ACC-expressed insulin-like growth factor 1 (IGF-1) receptor, the recombinant cytotoxin interleukin-13-pseudomonas exotoxin A, and autologous tumor lysate dendritic cell vaccine. These agents have shown modest clinical activity, although nonzero in the case of the immune checkpoint inhibitors. Clinical trials are ongoing to evaluate whether this clinical activity may be augmented through combinations with other immune-acting agents or targeted therapies."

Journal • Review • Adrenal Cortex Carcinoma • Endocrine Cancer • Genito-urinary Cancer • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Oncology • Solid Tumor • IGF1 • IL13

Study Of CP-751,871 In Combination With Exemestane In Postmenopausal Women With Hormone Receptor Positive Advanced Breast Cancer (clinicaltrials.gov) - P2; N=219; Terminated; Sponsor: Pfizer; Trial primary completion date: Nov 2011 ➔ Sep 2012

Clinical • Combination therapy • Trial primary completion date • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CTCs

A Review of Monoclonal Antibody-Based Treatments in Non-small Cell Lung Cancer. (PubMed, Adv Exp Med Biol) - "In this review, we have assessed studies focused upon the treatment of non-small cell lung cancer. Some therapies are approved, such as bevacizumab and atezolizumab, while some are still in clinical trials, such as ficlatuzumab and ipilimumab, and others have been rejected due to inadequate disease control, such as figitumumab."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Clinical achievements reached by interfering with the IGF1R-PI3K-PTEN-AKT-mTOR axis (AACR-NCI- EORTC 2011) - The development of inhibitors of the PI3K-AKT-mTOR & IGF1R axis

Review • Breast Cancer • Hematological Malignancies • Hepatocellular Cancer • Melanoma • Multiple Myeloma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Renal Cell Carcinoma

Study of CP-751,871 in combination with exemestane in postmenopausal women with hormone receptor positive advanced breast cancer (clinicaltrials.gov) - P2, N=213; Terminated (Due to business reasons); Completion date: Mar '12 -> Mar '13

Completion date • Trial delayed • Breast Cancer • Oncology

Pharmacokinetics and pharmacodynamics of figitumumab, a monoclonal antibody targeting the insulin-like growth factor 1 receptor, in healthy participants (J Clin Pharmacol) - PMID: 23400740; "Overall, figitumumab (10 or 20 mg/kg) demonstrated PK properties typical of IgG2 antibodies and produced substantial and sustained increases in IGF-1 (total and free), IGFBP-3, and insulin."

Preclinical • Oncology

Study of CP-751,871 in combination with exemestane in postmenopausal women with hormone receptor positive advanced breast cancer (clinicaltrials.gov) - P2, N=213; Terminated; Completion date: Mar 2013 -> Oct 2013

Trial completion date • Breast Cancer • Oncology

A phase I clinical trial and independent patient-derived xenograft study of combined targeted treatment with dacomitinib and figitumumab in advanced solid tumors (Clin Cancer Res) - KOL: Alex Adjei; P1, N=74; "Objective responses were seen in patients with ACC, ovarian carcinoma, and salivary gland cancer. Pharmacokinetic analysis did not show any significant drug-drug interaction. In the ACC xenograft model, figitumumab exerted significant antitumor activity, whereas dacomitinib did not. Figitumumab-sensitive tumors showed down-regulation of genes in the insulin-like growth factor-receptor-1 pathway."

P1 data • Lung Cancer KOL Tracker • US NSCLC KEE

Human colon cancer stem cells are enriched by insulin-like growth factor-1 and are sensitive to figitumumab (Cell Cycle) - CP-751,871 reduces CSC populations in colon cancer cell lines in vitro and reduces tumor growth in vivo; Results suggest that CP-751,871 has preferential activity against putative CSC populations, and may compliment current standard chemotherapeutic regimens that target cycling cells

Oncology

Insulin-like growth factor 1 (IGF-1R) protein expression (PE) and gene copy number (GCN) for discrimination of response and outcome to figitumumab in NSCLC (ASCO 2012) - Presentation time: Sat, Jun 2; 1:15 PM - 5:15 PM; Anticipated presentation at ASCO 2012

Anticipated data presentation • Non Small Cell Lung Cancer • Oncology

Study of CP-751,871 in combination with sunitinib in patients with advanced solid tumors (clinicaltrials.gov) - P1, N=75; Sponsor: Pfizer; Active, not recruiting; Completion date: Aug 2012 -> Sep 2012

Trial completion date • Oncology

Preliminary efficacy of the anti-insulin-like growth factor type 1 receptor antibody figitumumab in patients with refractory Ewing sarcoma (J Clin Oncol, Int J Oncol) - P1/2, N=138; A4021020; Median OS was 8.9 months; Pts with a pretreatment circulating free insulin-like growth factor (IGF) -1 lower than 0.65 ng/mL (n=14) had a median OS of 3.6 months, whereas those with a baseline free IGF-1 ≥ 0.65 ng/mL (n=84) had a median OS of 10.4 months (p<0.001)

P1/2 data • Oncology

Preliminary efficacy of the anti-insulin-like growth factor type 1 receptor antibody figitumumab in patients with refractory Ewing sarcoma (J Clin Oncol, Int J Oncol) - P1/2, N=138; A4021020; Median OS was 8.9 months; Pts with a pretreatment circulating free insulin-like growth factor (IGF) -1 lower than 0.65 ng/mL (n=14) had a median OS of 3.6 months, whereas those with a baseline free IGF-1 ≥ 0.65 ng/mL (n=84) had a median OS of 10.4 months (p<0.001)

P1/2 data • Oncology

Figitumumab plus exemestane versus exemestane as first-line treatment of postmenopausal hormone receptor-positive advanced breast cancer: A randomized, open-label phase II trial (SABCS 2011) - Presentation time: WEDNESDAY, DECEMBER 7, 2011, 5:00 pm - 7:00 pm; Abstract not available

P2 data • Breast Cancer • Oncology

Phase II trial of figitumumab in patients with refractory, metastatic colorectal cancer (mCRC) (ASCO 2011) - Presentation time: Mon June 6, 8:00 AM to 12:00 PM: A4021006, P2, N=168; 6mo OS=49.4 (38.8, 60.0), 44.1 (33.4, 54.9) for cohort A and B resp; The probability of was not significantly greater than 0.45 for either cohort; There was a trend toward longer median OS in pts with high levels of free-IGF-1; Overall, F 20 mg/kg was better tolerated than F 30 mg/kg

P2 data

Figitumumab plus exemestane versus exemestane as first-line treatment of postmenopausal hormone receptor-positive advanced breast cancer: A randomized, open-label phase II trial (SABCS 2011) - P2, N=113; A4021004; The addition of figitumumab to exemestane was tolerable but overall did not improve PFS compared with exemestane alone in pts eligible for this trial; A trend towards benefit with figitumumab combined with exemestane in pts without evidence of baseline metabolic syndrome (HbA1c <5.7%) was observed together with improved tolerability

P2 interim results • Breast Cancer • Oncology

IGF inhibitor adds no benefit, potentially harmful in advanced NSCLC (Cancer Network) - P3, N=681; NCT00596830; Sponsor: Pfizer; “The median overall survival with the study drug was 8.6 months compared with 9.8 months for chemotherapy alone, for a hazard ratio (HR) of 1.18 (95% confidence interval [CI], 0.99–1.40; P = .06). The median progression-free survival was 4.7 months with figitumumab and 4.6 months with chemotherapy, for an HR of 1.10 (95% CI, 0.93–1.32; P = .27). ORRs were 33% with figitumumab and 35% with chemotherapy alone.” 

P3 data • Non Small Cell Lung Cancer • Oncology

Phase II study of figitumumab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: clinical activity and molecular response (GORTEC 2008-02) (Ann Oncol) - P2, N=17; GORTEC 2008-02; Only two pts achieved stable disease at 6-8 weeks; Median OS & PFS were 63 and 52 days, respectively; Figitumumab downregulated IGF-1R at the surface of tumor cells with activation of the EGFR pathway, as shown by the upregulation of p-EGFR in tumor cells (p=0.016), & an increase in the plasma level of tumor growth factor-alpha (p=0.006)

P2 data • Oncology

Advances in antibody therapeutics targeting small-cell lung cancer. (PubMed, Adv Clin Exp Med) - "...Although the results of pembrolizumab, nivolumab, ipilimumab, and rovalpituzumab tesirine are inspiring, all of the clinical trials on these drugs are phase I/II and have been verified for further phase III clinical trials. It was demonstrated that chemotherapy in combination with bevacizumab can improve the progression-free survival (PFS) in phase III trials. The insulin-like growth factor-1 receptor (IGF-1R) is associated with a poor prognosis in SCLC, while the anti-IGF-1R monoclonal antibody figitumumab has a potential therapeutic value. Tarextumab, an antibody that blocks both Notch2 and Notch3 signaling, in combination with etoposide and platinum (EP) in patients with untreated extensive-stage SCLC, proved to be well-tolerated and showed dosedependent anti-tumor activity. The therapeutic effect of sacituzumab govitecan, BW-2 and lorvotuzumab mertansine in SCLC warranted further evaluation. Bec2/BCG as an adjuvant vaccination in patients with limited-disease SCLC..."

Journal • Review

Emerging immune targets for the treatment of multiple myeloma. (PubMed, Immunotherapy) - "...Other monoclonal antibodies that have shown efficacy in combination therapy include siltuximab (OR: 66%), indatuximab (OR: 78%), isatuximab (OR: 64.5%), pembrolizumab (OR: 60%), bevacizumab (OR: 70%), dacetuzumab (OR: 39%) and lorvotuzumab (OR: 56.4%). No OR was observed with monotherapy using BI-505, siltuximab, bevacizumab, AVE-1642, figitumumab, atacicept, milatuzumab, dacetuzumab, lucatumumab, IPH2101, lorvotuzumab, BT062 and nivolumab...A recent experience of CAR T-cell (B-cell maturation antigen) therapy in advanced MM has shown global response of 100%. The future of monoclonal antibodies and adoptive T cells for MM treatment seems promising."

Journal