Clinical Experience With IGF-1R Inhibition in Non-Gastrointestinal Cancers
Recent clinical experience with IGF-1R inhibition in the treatment of sarcomas and lung cancers provides valuable insights regarding the use of these agents for gastrointestinal cancers.
Sarcoma
Recent clinical experience with IGF-1R inhibition in the treatment of sarcomas and lung cancers provides valuable insights regarding the use of these agents for gastrointestinal cancers.
Sarcoma
Ewing sarcomas are characterized by a reciprocal (11;22)(q24;q12) translocation that generates an oncogenic fusion protein, EWS/FLI-1, which requires IGF-1R for transformation and which suppresses the expression of IGFBP-3. IGF-1R has been implicated in growth, metastasis, and angiogenesis in Ewing sarcoma and rhabdomyosarcoma, and IGF-1 activation is common in these malignancies.[20,21]
IGF-1R expression is elevated in neuroendocrine tumors (NETs). The tyrosine kinase inhibitor NVP-AEW541 inhibited NET growth and led to apoptotic changes in the cancer cells.[24] Based on strong preclinical data, a phase II study of MK-0646 (dalotuzumab), an anti–IGF-1R antibody, was conducted; 25 patients with metastatic well-differentiated NETs (15 carcinoids, 10 islet cell carcinomas) were given MK-0646 as monotherapy. In this study, 5 patients achieved stable disease for 24 weeks or longer (range, 6.25 to 10.5 months). The most common serious adverse event possibly related to MK-0646 was hyperglycemia (7 patients, 25%).[25] The authors appropriately concluded that there was insufficient evidence of efficacy in their preliminary study to merit further investigation of IGF-1R inhibitors in NETs. However, this study did not include concurrent systemic chemotherapy, which can be effective in pancreatic islet cell carcinomas. Increasingly, it is being recognized that the IGF-1 pathway may not represent the sole mechanism for oncogenic transformation, given the absence of activating mutations; rather, the pathway may complement other mitogenic and anti-apoptosis/resistance mechanisms. Therefore, single-agent IGF-1R inhibitors may not be adequate therapy in most solid tumors.
Non–small-cell lung cancer (NSCLC)
In a phase Ib/II study of figitumumab in combination with standard doses of paclitaxel(Drug information on paclitaxel) and carboplatin(Drug information on carboplatin), two complete responses in patients with NSCLC were observed in the phase I portion of the study.[26] In the phase II portion of the study, 156 treatment-naïve patients with stage IIIb/IV NSCLC were randomly assigned in a 2:1 ratio to receive either paclitaxel, carboplatin and figitumumab (PCI) or paclitaxel and carboplatin alone (PC); 54% of patients treated with PCI and 42% of patients treated with PC had objective responses. Sixteen of 23 patients assessable for efficacy in the nonrandomized single-arm extension cohort also responded to treatment. More responses occurred in patients with squamous cell histology (14 of 18 randomly assigned patients and 11 of 14 non-randomly assigned patients). Responses were also observed in two patients with squamous histology who received figitumumab on PC discontinuation. [27] Therefore a phase III trial was initiated with the same two arms in NSCLC. [28] In this trial, 88% had squamous cancer histology. Serious adverse events in the PCI arm included dehydration, hyperglycemia, and hemoptysis. Low pre-treatment body mass index and creatinine clearance were predictive of early death for patients receiving figitumumab. The trial was discontinued after 681 patients were recruited, as a result of the hazard ratio (HR) crossing the pre-specified futility boundary of 1.1 in favor of the PC arm. However, survival HR estimates favored PC in patients with low baseline levels of IGF-1 (minimum P = .006 for IGF-1 < 120 ng/mL; HR, 1.6) and favored PCI in those with high baseline levels of IGF-1 (minimum P = .13 for IGF-1 > 145 ng/mL; HR, 0.62). A phase III trial examining the effects of figitumumab in combination with erlotinib (Tarceva) as a second- or third-line treatment in patients with previously treated advanced NSCLC was also recently discontinued due to potential futility.
The above studies have provided some important lessons for the development of IGF-1R–targeted therapies in other cancer types, such as gastrointestinal cancers:
• Strong anti-tumor efficacy is seen in a limited population with IGF-1 pathway activation through mutations—eg, in Ewing sarcoma.
• Resistance or recurrence often follows response to IGF-1R–targeted agents.
• Experience in NSCLC suggests that multiple phenotypic and or molecular markers may be predictive of response (such as both squamous cell histology and high IGF-1 level).
• Single-agent IGF-1R inhibition may not be adequate, as noted in NET, and combination with chemotherapy may be needed.
• Combination strategies that target both EGFR and IGF-1R have not met with clinical success in NSCLC.
Gastrointestinal Cancers and IGF-1 Inhibition
Colorectal cancer
IGF-1R activation is crucial for the transforming activity of the epidermal growth factor receptor (EGFR). This interaction may be particularly important in CRC, in which EGFR inhibitors such as cetuximab(Drug information on cetuximab) (Erbitux) and panitumumab (Vectibix) are the standard of care.[29] In preclinical models of CRC, the combination of IGF-1R and EGFR inhibition resulted in enhanced growth arrest.[30] The results of a randomized phase II study in CRC evaluating IMC-A12 (cixitumumab) with or without cetuximab were recently published.[31] Patients with anti-EGFR antibody–refractory CRC (including mutant and wild-type [wt] K-ras tumors) were randomly assigned to treatment with either IMC-A12 as monotherapy or IMC-A12 in combination with cetuximab. The trial was further expanded, and an additional arm of patients with K-ras wt tumors was added after a patient with this genotype achieved a partial response to IMC-A12 plus cetuximab. Serious adverse events thought to be related to IMC-A12 included infusion-related reaction, thrombocytopenia, hyperglycemia, and pyrexia. Overall, 64 patients were enrolled in the three-arm study, and one patient demonstrated a partial response, with disease control lasting 6.5 months, but no additional antitumor activity was demonstrated. In 11 patients, correlative data were collected. Analysis of tumor samples by immunohistochemistry (IHC) revealed modest to strong IGF-1R staining in 3 of the 11 tumors. The one responding patient exhibited only low IGF-1R expression and no pAkt.[31] An additional large phase II/III study was performed in patients with irinotecan(Drug information on irinotecan) (Camptosar)-refractory CRC with K-ras wt who were treated with irinotecan and cetuximab ± MK-0646. The combination of cetuximab, irinotecan, and MK-0646 was well tolerated; efficacy data have not yet been published.[32]
IGF-1 expression was correlated with clinical outcomes in K-ras wt tumors treated with irinotecan and cetuximab. Progression-free survival in patients with IGF-1–negative tumors was superior to that in patients with IGF-1–positive tumors, suggesting that IGF-1 expression may be a prognostic factor for resistance in K-ras wt tumors treated with irinotecan and cetuximab.[33] IGF pathway polymorphisms were also associated with clinical outcomes in patients with K-ras wt tumors treated with cetuximab monotherapy.[34] These studies suggest that IGF-1 expression may identify a subgroup of patients with K-ras wt tumors who are likely to benefit from EGFR + IGF-1R–targeted treatments. However, no prospective study has yet assessed the effect of IGF-1R inhibition in CRC patients with high levels of IGF-1. Furthermore, most of the IGF-1R inhibitors currently in clinical trials are K-ras–independent; therefore, their activity in K-ras mutant CRC is also worthy of investigation.
Pancreatic cancer
Pancreatic adenocarcinoma has a dismal prognosis, with a 5-year survival rate of 5% for all stages combined. Gemcitabine(Drug information on gemcitabine) (Gemzar) has been the mainstay of treatment for the last ten years despite limited efficacy. The EGFR inhibitor erlotinib (Tarceva) results in a survival benefit when added to gemcitabine. However, resistance is common through cross-talk between EGFR and the IGF-1R pathways.[35] Increased IGF-1 and IGF-1R expression occurs in a number of gastrointestinal cancers, including pancreatic cancer.[29] In vivo inhibition of IGF-1R expression decreased pancreatic cancer growth in an orthotopic model.[36] Our study of genetic variations in the IGF-1R pathway demonstrated that SNPs within this pathway correlate with worse overall survival in patients with pancreatic cancer.[37] The prognostic value of one SNP in IRS1 was validated in a retrospective cohort of 706 pancreatic cancer patients at our institution.
Three randomized phase II studies are currently investigating IGF-1R–directed monoclonal antibodies in combination with gemcitabine for patients with advanced pancreatic cancer. At the MD Anderson Cancer Center, the monoclonal antibody MK-0646 is being investigated in a three-arm randomized phase II study of gemcitabine + MK-0646, gemcitabine + erlotinib + MK-0646, and gemcitabine + erlotinib (control arm). Thus far, 55 patients have been enrolled (out of a planned 100) and 11 (20%) confirmed partial responses have occurred. Interestingly, these have been sustained partial responses (one as long as 62 weeks) and only one of these has been in the control arm. In a preliminary analysis, no significant survival improvement was noted with the addition of erlotinib. Kindler et al reported the results of a randomized phase II study of gemcitabine + AMG 479 (an IGF-1R–directed monoclonal antibody), gemcitabine + AMG 655 (antibody against death receptor 5 [DR5]), and gemcitabine + placebo.[38] In a final analysis of this phase II trial, the 12-month overall survival was 39%, 20%, and 23%, in the AMG 479, AMG 655, and control arms, respectively, with a HR of 0.65 in favor of the study arms. A phase III study of gemcitabine ± AMG 479 is currently underway. In both these studies, the toxicities of the study agent have been tolerable, with thrombocytopenia, hyperglycemia, and neutropenia being the principal toxicities (10% to 20% grade 3 or 4 events). The Southwest Oncology Group (SWOG) is investigating the monoclonal antibody IMC-A12 in a phase II randomized study of gemcitabine and erlotinib ± IMC-A12. Toxicity results of this study have been reported and appear to parallel the results of the above two studies. Further development of IGF-1R inhibitors in pancreatic cancer will depend on the results of the above studies.
Other clinical trials that are ongoing in gastrointestinal cancers include a trial of IMC-A12 in combination with sorafenib(Drug information on sorafenib) (Nexavar) for hepatocellular cancer (California Consortium) and a trial of paclitaxel ± IMC-A12 for metastatic esophageal cancer (Fox Chase Cancer Center). Efficacy data from these studies have not yet been reported.
While it is premature to draw conclusions from the above studies, it is evident that the combination of IGF-1R inhibitors with chemotherapy is tolerable and without serious toxicity. Hyperglycemia is not clinically significant even in diseases such as pancreatic cancer. In CRC, there does not appear to be a meaningful clinical synergism between the EGFR and the IGF-1R inhibitors.
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