In this phase II trial, IMC-A12, alone or in combination with cetuximab, did not demonstrate meaningful antitumor activity in advanced, anti-EGFR antibody-refractory CRC. Of 64 patients treated, no responses were observed in 63. One patient did achieve a durable partial response to IMC-A12 and cetuximab. Before study entry, this patient with CRC and pulmonary metastases had experienced disease progression on both an oxaliplatin- and an irinotecan-containing regimen before being treated with the combination of irinotecan and cetuximab. He experienced documented disease control to the cetuximab/irinotecan regimen, and then he experienced disease progression after 8.5 months, manifested as growth of pulmonary lesions on computed tomography scan and an increase in serum carcinoembryonic antigen levels. Four weeks after disease progression occurred on this combination, the patient was then enrolled in arm B and received the combination of cetuximab and IMC-A12. The schedule of cetuximab on this trial of 500 mg/m2 every 2 weeks differed from the weekly cetuximab 250 mg/m2 he had previously received; we consider it extremely unlikely, however, that this modified dose and schedule constituted the basis for the therapeutic efficacy. It is unclear at this time whether the continuation of cetuximab contributed to the observed response or whether single-agent IGF-1R inhibition would have been sufficient to cause the tumor regression observed. In addition, as the patient was treated with cetuximab immediately after progression on a cetuximab-containing regimen, it is unlikely that the response observed would have been seen with cetuximab treatment alone. On retrospective analysis of archived tumor tissue, the tumor of this patient was KRAS wild type.
Given the unequivocal durable response observed in this patient and the recent data demonstrating that the clinical activity of EGFR-directed therapies is confined to patients whose tumors are KRAS wild type, we amended the study to add a third treatment arm that consisted of patients whose tumors were KRAS wild type and who had experienced a prior response of at least 24 weeks' duration. In this genetically and clinically selected population, no additional responses were observed and only a single patient exhibited stable disease of at least 12 weeks. Although PFS and OS were higher on arm C, this arm was selected to include KRAS wild-type disease plus a response to prior cetuximab for at least 5.5 months; the improved outcomes in this nonrandomized arm may be a reflection of more indolent disease biology.
Given the promising preclinical data with IGF-1R-directed therapies,1–3,6
why was the response rate to the combination of IMC-A12 and cetuximab so low in CRC? KRAS
is a key downstream effector of EGFR and other receptor tyrosine kinases. KRAS
mutations are found in approximately 40% to 50% of CRC, most commonly at the G12/G13 codons.18–20
These mutations result in impaired intrinsic and guanosine 5′-triphosphatase activating proteins–mediated guanosine 5′-triphosphate hydrolysis and, thus, lead to constitutive expression of high levels of activated RAS–guanosine 5′-triphosphate. Several retrospective assessments of KRAS
status in phase III, randomized trials of anti-EGFR–directed therapies have confirmed that activity with these agents is restricted to patients with KRAS
As noted previously, however, the objective response rate is relatively low among patients with wild-type KRAS
These data indicate that KRAS
wild-type status is necessary but not sufficient for response with these agents. More recent data suggest that BRAF
mutations may also confer resistance to therapy;18
in our study, one of 19 tumor specimens () tested retrospectively for I mutation was positive for the V600E mutation.
As the mitogen-activated protein kinase pathway is one of the key effectors of both EGFR- and IGF-1R–mediated cell growth, it would be reasonable to hypothesize that, as was observed with cetuximab, the clinical efficacy of IMC-A12 may also be restricted to patient whose tumors are wild type for KRAS and BRAF. Consistent with this hypothesis, the one patient who did respond to the combination of IMC-A12 and cetuximab had a tumor that was wild type for KRAS, NRAS, BRAF, and PIK3CA. Given the low response rate observed, the results of the study suggest that RAS wild-type status may be required but not sufficient to confer IGF-1R dependence.
A second possible explanation for the limited efficacy observed in this trial is that IGF-1R may not have been highly activated in the patients enrolled. To address this possibility, we determined the level of expression of IGF-1R by IHC. We also assessed for AKT pathway activation by performing IHC for pAKT expression. In this analysis, we observed modest to strong staining for IGF-1R in only three of 11 tumors. Notably, the one responding patient exhibited only 1+ staining for IGF-1R and had no detectable staining for phosphorylated AKT. It should be highlighted that total IGF-1R IHC expression may be a poor indicator of the degree of IGF-1R activation.
In summary, our correlative data and the limited clinical efficacy of IMC-A12 in this study suggest that additional preclinical work will be required to identify predictors of IGF-1R dependence in CRCs, possibly with emphasis on downstream signaling elements, such as AKT and/or PI3K. Novel assays and methodologies will also be needed which can, with high sensitivity and specificity, identify tumors with high levels of IGF-1R activation. This will be a challenge, as IGF-1R activation is typically ligand-dependent in CRC, and mutation and amplification of this receptor in human tumors has not been reported with high frequency.
Our data indicate that the safety of the anti-EGFR and anti-IGF-1R combination does not constitute a major impediment to proceeding with additional studies in different tumor types. No evidence of synergistic toxicity was observed, and the toxicities encountered appear to be comparable to the toxicities that would have been expected from the individual agents alone.
The interpatient pharmacokinetic differences between arms A and B patients appear to be minor and unlikely to be clinically relevant. Importantly, it is unlikely that dose adjustment would be necessary when administering IMC-A12 to patients with mild or moderate diabetes mellitus, although all patients enrolled on the trial had to have a fasting glucose less than 120 mg/dL, which suggests that this selected population had better glucose control.
In conclusion, IMC-A12 alone and in combination with cetuximab was inactive in all but one of 64 patients treated. Study modification to assess a more select population of patients who were KRAS wild type and who had experienced a prolonged response to an anti-EGFR–directed therapy, however, failed to elicit evidence of additional clinical activity. This negative trial does not preclude the potential usefulness of IGF-1R inhibitors when used in combination with active chemotherapy or other targeted pathway inhibitors.