Clinical Cancer Research Vol. 12, 4441s-4445s, July 15, 2006
© 2006 American Association for Cancer Research
Novel Agents in the Treatment of Lung Cancer: Advances in EGFR-Targeted Agents |
Epidermal Growth Factor Receptor Inhibitors in Development for the Treatment of Non–Small Cell Lung Cancer
John V. Heymach1,2,
Monique Nilsson2,
George Blumenschein1,
Vassiliki Papadimitrakopoulou1 and
Roy Herbst1,2
Authors' Affiliations: Departments of 1 Thoracic/Head and Neck Oncology and 2 Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas
Requests for reprints: John Heymach, Department of Thoracic/Head and Neck Medical Oncology, M.D. Anderson Cancer Center, Unit 432, 1515 Holcombe Boulevard, Houston, TX 77030-4009. Phone: 713-792-6363; Fax: 713-796-8655; E-mail: jheymach{at}mdanderson.org.
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Abstract
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The epidermal growth factor receptor (EGFR) inhibitors erlotinib, gefitinib, and cetuximab have undergone extensive clinical testing and have established clinical activity in non–small cell lung cancer and other types of solid tumors. A number of newer inhibitors are currently in clinical development with different spectra of activity or mechanisms of receptor inhibition. These include monoclonal antibodies, such as panitumumab and matuzumab; dual inhibitors of EGFR and vascular endothelial growth factor receptor, such as ZD6474 and AEE788; inhibitors of multiple EGFR family members, such as lapatinib; and irreversible inhibitors, such as canertinib and HKI272. Preclinical studies suggest that several of these agents may have activity in tumors refractory to erlotinib or gefitinib. Among these agents, ZD6474 has undergone the most extensive clinical testing. The antitumor activity of ZD6474 in these two randomized phase II clinical trials in patients with non–small cell lung cancer was felt to be sufficiently promising to warrant phase III clinical testing. Several of the other EGFR inhibitors are also undergoing advanced clinical testing, either alone or in combination with other agents. EGFR has now been validated as a clinically relevant target, and several different types of agents inhibiting this receptor are currently in development. Future research will be needed to elucidate the role of these agents in patients with EGFR inhibitor–naive and EGFR inhibitor–refractory disease, to define the molecular characteristics that predict response, and to determine whether these drugs should be used in combination with other targeted agents or chemotherapy.
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Potential Benefits of New EGFR Inhibitors
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Recent phase III clinical trials have shown that agents targeting the epidermal growth factor receptor (EGFR) pathway can prolong survival in patients with non–small cell lung cancer (NSCLC) and have significant activity in other types of solid tumors as well (1, 2). In patients with previously treated NSCLC, a 2-month benefit in overall survival was observed for patients treated with erlotinib compared with patients in the placebo control arm (1). In the Iressa Survival Evaluation in Lung Cancer trial, no significant prolongation in overall survival was observed for the overall NSCLC population, although certain populations did seem to benefit (3). Although the currently available EGFR inhibitors erlotinib, gefitinib, and cetuximab represent important advances, the overall magnitude of this benefit has been modest, and in almost all cases, resistance to EGFR inhibitors eventually emerges, even in patients initially sensitive to treatment. This raises the question of whether additional benefit may be derived from the use of newer EGFR inhibitors currently in development (Table 1
). Potential advantages of these new agents include:- 1. Improved potency or pharmacokinetics of EGFR inhibition. Gefitinib and erlotinib have both been shown to at least partially inhibit EGFR phosphorylation in skin biopsies taken from patients undergoing treatment (4, 5), although the degree of EGFR inhibition in NSCLC tumor tissue is not known. Agents with greater potency, improved pharmacokinetics, or higher tumor tissue concentrations may provide a more sustained blockade of EGFR signaling and potentially greater benefit.
- 2. Inhibition of multiple EGFR family members. EGFR signaling occurs through both receptor homodimerization and heterodimerization with other EGFR (erbB) family members, particularly Her2 and Her3 (6, 7), and disruption of these interactions may increase the biological effects of EGFR blockade.
- 3. Inhibition of erlotinib- or gefitinib-resistant mutations. Recent studies have revealed several potential mechanisms for the development of resistance to EGFR tyrosine kinase inhibitors. These include secondary mutations in EGFR, such as T790M, that hinder the binding of erlotinib and gefitinib to the ATP-binding pocket within the EGFR tyrosine kinase domain (8, 9). In vitro data suggest that this resistance can be overcome using irreversible inhibitors, such as HKI272 (10). Agents targeting the extracellular domain of EGFR would be predicted to be less susceptible to these secondary mutations, although this hypothesis has not yet been evaluated in the clinical setting.
- 4. Dual inhibition of vascular endothelial growth factor (VEGF) and EGFRs. EGFR inhibitors have been shown to exert antiangiogenic effects by decreasing the expression of proangiogenic factors (VEGF, bFGF, and IL-8; ref. 11) and through direct effects on tumor endothelium (12). These antiangiogenic effects may be substantially increased by blockade of the VEGF and EGFR pathways simultaneously. Preclinical data suggest that one agent inhibiting these two pathways (ZD6474) may have activity in gefitinib- or erlotinib-resistant NSCLC xenograft tumors (13, 14).
- 5. Additive or synergistic activity in combination with chemotherapy. To date, the addition of EGFR inhibitors (erlotinib or gefitinib) to standard chemotherapy has not improved overall survival compared with standard chemotherapy alone in patients with previously untreated NSCLC (15, 16). EGFR inhibitors have, however, shown benefit when combined with standard chemotherapy in patients with colorectal cancer (2) or pancreatic cancer (17). It is not known if these disparate results are due to the particular agents combined in the NSCLC studies or to differences in the biology of these tumor types.
Selected EGFR inhibitors in development are briefly discussed below. They are divided into small-molecule inhibitors of the EGFR tyrosine kinase domain (reversible and irreversible), dual EGFR/VEGFR inhibitors, and antibodies directed against the extracellular domain of EGFR.
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Reversible EGFR Inhibitors
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Lapatinib is an oral dual kinase inhibitor that targets both EGFR and Her2. In phase I testing in 67 heavily pretreated patients with EGFR and/or Her2-expressing tumors, lapatinib was well tolerated at doses ranging from 500 to 1,600 mg once daily, with diarrhea and rash as the most frequently observed adverse effects. Clinical activity was observed, with partial responses observed in four patients with trastuzumab-resistant breast cancers and prolonged stable disease for >6 months in an additional 10 patients (18). In a randomized phase II multicenter trial comparing two schedules and doses of lapatinib in patients with chemo-naive advanced or metastatic NSCLC, there were no significant drug-related toxicities. Efficacy results from this trial are pending (19).
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Irreversible EGFR Inhibitors
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EKB-569 is an oral, irreversible inhibitor of the EGFR and Her2 tyrosine kinases. A phase I study was conducted in 41 patients with advanced-stage tumor types known to overexpress EGFR using two schedules: daily for 14 days followed by a 14-day washout and continuously for 28 days. On both the intermittent and continuous dosing schedules, dose-limiting toxicity was grade 3 diarrhea. Other adverse events reported were rash, asthenia, anorexia, nausea, stomatitis, and vomiting. No objective tumor responses were reported. EKB-569 is currently being evaluated in NSCLC and in combination with chemotherapy for colorectal cancer.
Canertinib (CI-1033) is an oral, irreversible inhibitor of all four members of the ErbB receptor family. In a phase I dose escalation study of 32 patients with advanced tumors, canertinib was given at doses up to 560 mg daily on a 14-day on/7-day off schedule. No objective responses were observed, although six patients had stable disease for >3 months. Primary adverse events included grade 1 to 2 rash, nausea, and stomatitis. At the higher doses, the dose-limiting toxicities were diarrhea and edema; the maximum tolerated dose was 450 mg (20). Minimal antitumor activity was seen in patients with platinum-refractory ovarian cancer (21).
HKI272 is an irreversible tyrosine kinase inhibitor with dual activity against EGFR and Her2. In vitro studies have shown activity of HKI272 in NSCLC cell lines with acquired resistance to gefitinib (10). In preclinical xenograft studies, HKI272 significantly reduced the growth of HER2- and EGFR-dependent tumors when given at doses between 10 and 40 mg/kg/d (22). Phase I trials to determine safety and tolerability are presently recruiting patients.
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Dual EGFR/VEGFR Inhibitors
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ZD6474 is an oral, quinazoline derivative inhibitor of EGFR and VEGFR. Phase I clinical evaluation has shown ZD6474 to be generally well tolerated, with a pharmacokinetic profile appropriate for once-daily oral dosing and a half-life of >120 hours (23). Phase II evaluation of ZD6474 has included two randomized studies of patients with NSCLC. In one of these trials, the efficacy of ZD6474 monotherapy (300 mg) was compared with that of the EGFR inhibitor gefitinib in previously treated patients. The adverse event profile of ZD6474 was similar to that seen in previous trials and included rash, diarrhea, and asymptomatic QTc prolongation. A statistically significant improvement in time to progression was observed for ZD6474 compared with gefitinib (11.9 versus 8.1 weeks, P = 0.011). In a second trial, 127 patients with platinum-refractory NSCLC were treated with ZD6474 (100 or 300 mg) or placebo, in combination with docetaxel (75 mg/m2 by i.v. infusion every 21 days; ref. 24). Preliminary results show a median time to progression was 12.0 weeks for docetaxel alone, 18.7 weeks for ZD6474 100 mg plus docetaxel (P = 0.07 for comparison with control arm), and 17.0 weeks for ZD6474 300 mg plus docetaxel (P = 0.42). A randomized trial of ZD6474 in combination with carboplatin and paclitaxel is also ongoing (25). Based on these results, phase III trials are currently being planned.
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Monoclonal Antibodies Targeting EGFR
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Panitumumab (ABX-EGF) is a fully humanized monoclonal antibody directed against EGFR that binds with high affinity (Kd = 5 x 10–11; ref. 26). It has shown activity as a single agent and in combination with cytotoxic chemotherapy in colorectal carcinoma. In a phase I trial, 96 patients with solid tumors were treated with panitumumab monotherapy at various doses and schedules (27). Panitumumab was well tolerated and showed clinical activity, including partial responses and stable disease. These results were particularly encouraging in colorectal cancer, as five partial responses were seen in 39 colorectal patients treated. Grade 3 skin toxicities were the most frequently reported grade 3 to 4 adverse event (27). A randomized phase II study is currently evaluating the activity of carboplatin/paclitaxel with or without the addition of panitumumab in patients with chemotherapy-naive advanced NSCLC. This study has completed accrual with results pending.
Matuzumab (EMD72000), a humanized monoclonal antibody directed against EGFR, has been shown to have antitumor activity in xenograft models. Phase I clinical trials investigating safety and pharmacokinetics have been conducted in patients with advanced-stage disease treated weekly with 400, 800, 1,200, or 1,600 mg of matuzumab. Overall, the doses tested were well tolerated with toxicities, including grade 1 to 2 diarrhea and rash. The half-life was 
110 hours. To examine biological activity, skin biopsies obtained before treatment and then again on day 29 were evaluated by immunohistochemistry for phospho-EGFR and phospho-mitogen-activated protein kinase. Complete inhibition of EGFR and mitogen-activated protein kinase activation was observed at the 1,200 and 1,600 mg doses, respectively (28). In a phase I study in which patients with advanced esophagogastric adenocarcinomas were treated with 400 or 800 mg matuzumab and ECX (epirubicin, cisplatin, and capecitabine), overall response rates at 400 and 800 mg were 57% and 43%, respectively, suggesting that the combination has antitumor activity (29). A phase II study evaluating the efficacy of matuzumab in combination with pemetrexed in advanced NSCLC is ongoing.
Pertuzumab (2C4) is the first in a new class of therapeutic agents designed to inhibit the dimerization of HER2 with EGFR and other HER tyrosine kinases. A phase I study found pertuzumab to be safe and well tolerated, with the major toxicities being diarrhea and rash (30). A randomized phase II trial was initiated to evaluate the activity of pertuzumab in breast cancer. Overall, response or stable disease was observed in <8% of patients (31). A phase II study was also conducted to determine the efficacy of pertuzumab in chemotherapy-naive patients with hormone-refractory prostate cancer. No prostate-specific antigen responses were observed (32). Phase II evaluation of pertuzumab in refractory or recurrent ovarian cancer yielded somewhat more promising results, with objective tumor responses or CA125 responses in 15% of patients (33). Based on the preclinical studies showing that inhibition of EGFR by multiple mechanisms may have an additive effect, and that the activity of erlotinib in combination with pertuzumab is superior to that of either agent alone (34), the combination of pertuzumab and erlotinib is currently undergoing phase II clinical evaluation.
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Concluding Remarks
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EGFR inhibitors now have an established role in the treatment of NSCLC and several other tumor types, but benefits have generally been modest thus far, and tumors have inevitably developed resistance over time. Fortunately, over the past several years, two major developments have occurred that give reason to believe that these therapies can be improved. The first is our rapidly expanding understanding of the biological mechanisms underlying the sensitivity of a tumor to EGFR inhibitors and of how therapeutic resistance emerges. The second is the development and clinical testing of multiple new EGFR inhibitors, including reversible and irreversible tyrosine kinase inhibitors, dual VEGFR/EGFR inhibitors, and monoclonal antibodies. The convergence of these two developments provides the possibility for more specific and effective therapeutic regimens for patients with NSCLC and other tumor types.
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Open Discussion
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Dr. Tim Eisen: ZD6474 is an oral antiangiogenic agent. Looking at long-term pharmacokinetics, could it inhibit its own absorption and could that affect the way that it works?
Dr. Heymach: There is no evidence that it induces its own metabolism, if that is what you are asking. It has a 120-hour-plus half-life; steady-state levels are reached after roughly 15 days or so. Upon achieving steady state, the levels appear to hold steady. We've looked at it in our trials in combination with chemotherapy as well.
Dr. Eisen: You said that with ZD6474 VEGF inhibition was achieved more effectively at 100 mg than EGFR inhibition.
Dr. Heymach: From preclinical studies, we know the IC50 tends to be 5- or 10-fold lower.
Dr. Eisen: But is it not theoretically possible that you don't need as complete inhibition if you are inhibiting multiple pathways?
Dr. Heymach: Right. We are making assumptions based on the IC50 from preclinical studies, but translating that into what has happened clinically is something we are trying to assess quantitatively with tumor biopsies. We have a clinical trial right now with pre- and posttreatment biopsies to address just this issue.
Dr. Thomas Lynch: Why was there no bleeding?
Dr. Heymach: One possibility is that it will act just like bevacizumab, and we just haven't looked at enough patients.
Dr. Lynch: But Dave Johnson saw bleeding in his phase II bevacizumab-carboplatin/paclitaxel study.
Dr. Heymach: Yes, it was roughly 10% before selection, if I remember correctly. It was 6 out of 66 patients. So if the assumption, then, is that the bleeding occurs in large tumors, which undergo a lot of necrosis quickly in the setting of combination carboplatin and paclitaxel, then we may not have big enough patient numbers yet. Or something could happen when you inhibit both VEGF and EGFR that may put the brakes on the process. There may be a real biologic difference. The bottom line is we don't know. But we haven't seen any evidence of bleeding like that in the bevacizumab trial. We did have one case of hemoptysis that occurred by a completely different mechanism in the 006 trial. It was a cavity around an area that a pneumonia formed. I don't know that this has been seen with other VEGF inhibitors. So this suggests that there may be some impact on tissue regeneration or wound healing, as seen with bevacizumab.
Dr. Panos Fidias: Initially there were a couple of patients with photosensitivity reactions. What happened with that?
Dr. Heymach: We believe those were all at the 300 mg dose. The major reason for discontinuing at the 300 mg dose was the rash. As Dr. Fidias' question implied, there are actually two components to the rash. It wasn't exclusively the EGF receptor acneiform rash, but there was also a photosensitivity component to it as well.
Dr. Fidias: My other question is related to that. In the preclinical model, the combination of erlotinib plus bevacizumab was the same as the big dose of ZD6474. But you would expect, clinically, that if inhibition of both pathways is important, it would do better. It didn't do better. It's probably because of the toxicity then.
Dr. Heymach: In our preclinical models, bevacizumab/erlotinib and ZD6474 always behaved similarly. The one exception being that in the erlotinib progressors, ZD6474 looks a little better than bevacizumab plus erlotinib. So maybe those particular tumors are more resistant to erlotinib specifically.
Dr. Fidias: But it is difficult clinically to give that kind of dose to equal the erlotinib plus bevacizumab.
Dr. Heymach: It is hard to match up doses. We have spent a lot of time addressing how we should dose these things. Instead of trying to match on an equimolar stoichiometric basis, we use the established maximum doses that these drugs can be given to mice. We do a regimen where we actually do dose reductions if the mice lose weight on the drug.
Dr. Kwok-Kin Wong: In your preclinical models, do you have any biological measure to show that you are hitting the VEGF pathway in terms of angiogenesis and not just hitting the EGFR pathway?
Dr. Heymach: We are in the process of analyzing these tumors right now.
Dr. Glenwood Goss: I know you presented the toxicity data, but could you just give us your impression? At the 300 mg dose, is the toxicity tolerable in the majority of patients?
Dr. Heymach: It's a tough regimen when given at the higher dose in combination with docetaxel. I think that the 100 mg dose was dramatically better tolerated in combination with docetaxel; in fact, it did as well as placebo. The 300 mg had significantly greater toxicity, particularly rashes.
Dr. Goss: So you can't push the dose further?
Dr. Heymach: In combination with docetaxel in particular, there is probably an idiosyncratic reaction that occurs. Docetaxel has some skin toxicity itself. In combination with carboplatin and paclitaxel, we haven't had skin toxicity issues at the 300 mg dose, at least to the same extent.
Dr. Goss: There is the ongoing question of adequate EGFR blockade with the 250 dose of gefitinib. So if the toxicity is just related to docetaxel, there may be some room to push that dose.
Dr. Heymach: An alternative approach is to use the lower concentration during chemotherapy and then escalate to a dose where you're getting dual pathway inhibition in a monotherapy phase.
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Footnotes
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Presented at the Third Cambridge Conference on Novel Agents in the Treatment of Lung Cancer: Advances in EGFR-Targeted Agents, September 23-24, 2005 in Cambridge, Massachusetts.
Received 2/ 7/06;
accepted 4/19/06.
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Abstract
Potential Benefits of New...
