Activity of EGFR Inhibitors in Combination With Other Chemotherapeutic Agents

Combining treatment modalities remains the main approach for cancer therapy, but more emphasis on rational, mechanism-based combinations (73-75) as opposed to empirical testing (76) should be the aim. Although in vitro profiling provides much of the information needed to ascertain the benefits (and just as important, indicate contraindicated combinations) and provide some information on administration regimens (77), animal models can be used to profile potential combinations of agents gaining information on the effect of dose and schedule on both anti-tumor effect and tolerability in the context of drug metabolism by the host (78). Table 5 presents a concise review of some of the studies where the combination of an EGFR inhibitor and another form of cancer therapy has been evaluated. A variety of cell lines have been used in both subcutaneous and orthotopic locations. In general, the combinations involving the EGFR inhibitor are superior to either agent alone. However, careful inspection of the data is required in that often dose reductions are needed, and under these circumstances the anti-tumor response of the combination may not be greater than the conventional agent administered at an optimal dose.

A thorough evaluation of the EGFR inhibitor gefitinib as a combination partner for conventional agents (65) indicated that the anti-tumor activity of most of the conventional agents tested (cisplatin, carboplatinum, paclitaxel, doc-etaxel, doxorubicin, or edatrexate) was potentiated by concomitant gefitinib; vinorelbine combinations were too toxic and no potentiation was observed with gemcitabine. However, dose reduction of gefitinib was required in order to produce an acceptably tolerated combination treatment. Combination effects were observed irrespective of the extent of pEGFR expression.

Table 3 presents the activity of NVP-ADL681-NX in combination with Taxol in the NCI-H596 tumor model in nude mice. NVP-ADL681-NX was administered at its optimal dose and schedule (75 mg/kg twice daily [bid]; T/C 29%) whereas Taxol was administered at a dose and schedule (15 mg/kg once per

Fig. 5. (continued) were determined after 27 d. (A) The response of each individual tumor was assigned to the categories based on changes in volume over the course of the experiment. * p < 0.025, Crochan-Mantel-Hansel test with subsequent ranking and allowance for multiple comparisions by Holm's procedure. (B) Tumor volumes and body weights were determined two to three times per week. *p < 0.05 vs controls (analysis of variance on ranks and Dunn's test) (R. Brandt and T. O'Reilly, unpublished data).

Table 5

Selected Examples of Tumor Models Used to Preclinically Evaluate EGFR-Family Inhibitors: Combinations

Reference

Tumor

Compound Analysis methods

Comments

Colo320DM, Lovo, WiDR colon

OSCC cell lines HSC2 and HSC3

Human NSCLC A549, SK-LC-16, breast MDA-MB468, human mesothelioma (JMN) Orthotopic model of oral cancer, JMAR cells were implanted into the tongues of nude mice FaDu human squamous cell carcinoma

Gefitinib CPT-11 WB, TV

Gefitinib RT In vitro, TV, IHC

Gefitinib RT

PKI166 Taxol®

BIBX1382BS RT

Renal bone metastasis intra- PKI166 Taxol® tibial injection of RBM1-IT4, established from a human RCC bone metastasis

Survival, IHC, TM, apoptotic fraction

TV, doubling time, BrdU, Ki67 staining

NB and WB, histology, ICC, radiology

Combination produced supra-

additive inhibitory effect on WiDR, tumor shrinkage in Lovo whereas no additive effect in COL0320DM Combination caused growth inhibition and tumor regression of OSCC tumors IHC revealed gefitinib to cause decreased tumor cell proliferation when combined with RT Gefitinib significantly enhanced the antitumor action of RT, without significant adverse effects.

Combination therapy prolonged survival by increasing apoptosis

Combination prolongs tumor growth delay, but BIBX1382BS did not reduce the radiation dose needed to control local tumor growth Combination enhanced antitumor effect

88 GEO colon

100 GEO colon

89 A431 epidermoid

ZD6474, a In vitro, TV, IHC

VEGF-R (flk-l/KDR) EGFR "dual" inhibitor Taxol® ZD6474, a In vitro, TV, IHC

VEGF-R (flk-l/KDR) EGFR "dual" inhibitor SC-246, a COX-1/2 inhibitor PKA-1 antisense

Gefitinib RT In vitro, TV, IHC

96 PC-3MM2 orthotopically PKI166 Taxol® TM, IHC, radiology implanted in the tiba

Combination potentiatiate inhibition of angiogenesis, resulting in tumor regression

Triple combination produced a cooperative antitumor effect, with IHC revealed inhibition of vessel formation and expression of COX-2 and VEGF

Gefitinib potentiates the antitumor effect of single and multiple fractions of radiation; Gefitinib reduced tumor vascularity, and EGF-induced VEGF protein and mRNA Combination reduced the incidence and size of bone tumors and destruction of bone, demonstrated increased inhibition of phosphorylation of EGFR on tumor and endothelial cells and induced significant apoptosis and endothelial cells within tumor lesions versus PKI166 alone

( Continued)

Table 5 (Continued)

Reference

Tumor

Compound

Analysis methods

Comments

CWR22 androgen-depend-ent and -independent prostate cancer

GEO colon A549 lung

Gefitinib bicalutamide (antiandrogen) carboplatin; paclitaxel

Gefitinib RT

Coadministration of gefitinib with a suboptimal dose of bicalutamide superior to a high-dose of bicalutamidealone. Reduced tolera-bility of combination. Combination increased the activity of carboplatin and paclitaxel Combination resulted in a significant improvement in survival, tumor growth inhibition accompanied by a significant potentiation in the inhibition of TGF-a, VEGF, bFGF within the tumor; reduction of antiangiogenisis

HCC, hepatocellular carcinoma; IHC, immunohistochemistry; NB, northern blot; RT, radiotherapy; TM, tumor mass; TV, tumor volume; WB, western blot; OSCC, oral squamous cell carcinoma.

week) that results in suboptimal anti-tumor activity (T/C 48%). The combination resulted in a clear trend (not statistically significant) to better activity (T/C 2%) than either agent alone whereas toxicity (as judged by body weights and survival) was approximately the same as that seen when NVP-ADL681-NX was given alone. Other combinations were found to be less effective (e.g., NVP-ADL681-NX 38 mg/kg bid + Taxol 15 mg/kg once per week) or even more toxic (e.g., NVP-ADL681-NX 75 mg/kg bid + Taxol 5 mg/kg three times per week). Thus it can be concluded that combination of NVP-ADL681-NX may result in improved anti-tumor activity. However, the dose and schedule used needs to be chosen with care to optimize the anti-tumor activity while preventing unwanted toxicity.

Many studies have indicated the potential of EGFR inhibitors as a combination agent for radiotherapy (79), and a mechanism of action appears to be emerging: the signal cascade initiated by EGFR activation acts to facilitate survival and proliferation after ionizing radiation; consequently the action of EGFR inhibitors (inducing apoptosis, cell cycle arrest, and interfering with DNA repair) can act both on the tumor cell and also on the stromal compartment of tumors, potentiating the effects of ionizing radiation (79). However, the disappointing and, based on preclinical data, unexpectedly poor anti-tumor response in combination trials in patients (12,80) suggests that the predictive quality of preclinical data on combination therapy may be even lower than that for monotherapy. The reasons for this discrepancy are clearly unknown, but given the extra complication of a combination partner are likely to be multiple and complex.

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