The Evolving Role of Cetuximab in Non–Small Cell Lung Cancer

Cetuximab (C225, Erbitux) is a chimeric human-mouse monoclonal antibody that targets the epidermal growth factor receptor (EGFR), which is frequently overexpressed in non–small cell lung cancer (NSCLC). Cetuximab has a high affinity for the extracellular ligand binding domain of the EGFR, leading to receptor internalization, inhibition of phosphorylation, and subsequent blockage of downstream signaling (1). In preclinical models, cetuximab showed antitumor activity against a variety of tumors and was shown to enhance cytotoxicity of both chemotherapy (particularly cisplatin and paclitaxel) and radiation without augmenting toxicity (2).

Cetuximab is administered at a loading dose of 400 mg/m² followed by a maintenance dose of 250 mg/m² weekly. Single-agent toxicities are primarily skin rash and hypersensitivity reactions. Cetuximab is approved by the U.S. Food and Drug Administration for patients with refractory colon cancer alone or in combination with irinotecan (3). More recently, a phase III study of radiotherapy with or without cetuximab in patients with locally advanced head and neck cancer showed a significant survival advantage in favor of cetuximab-treated patients (4). This study led the Food and Drug Administration to approve the use of this combination in this setting.

In this review, we discuss the available data for cetuximab in first- and second-line NSCLC and some of the ongoing clinical trials. We also discuss differences in the mechanism of action between cetuximab and the oral tyrosine kinase inhibitors gefitinib and erlotinib, which may have implications for how these agents are used in this disease.

The first clinical trial to explore cetuximab in NSCLC was conducted by investigators at the M.D. Anderson Cancer Center. Patients with refractory NSCLC, defined as progressive disease during first-line platinum-based chemotherapy or within 3 months of its completion, received docetaxel at a dose of 75 mg/m² every 3 weeks in combination with cetuximab at the standard dose and schedule (5). All 54 patients enrolled were positive for EGFR by immunohistochemistry. Among 47 evaluable patients, the authors reported a 28% response rate and a median survival of 7.5 months.

More recently, the only phase II trial of cetuximab as a single agent in recurrent NSCLC was reported (6). Patients treated with at least one prior regimen were eligible. Although both EGFR-positive and EGFR-negative patients were enrolled, the vast majority (60 of 66) had EGFR-positive tumors. A total of 66 patients were entered, all of whom had a performance status of 0 to 1. Adenocarcinoma was the most common histology and ∼20% of patients were never smokers. Most patients (55 of 66) had received either one or two prior regimens. Three patients had an objective response (4.5%) and 20 patients achieved disease stabilization. Median survival and 1-year survival rates were 8.1 months and 41%, respectively. Toxicities were mild, with only 6% of patients experiencing grade 3/4 rash.

A subsequent analysis of EGFR mutations was done in 39 of 43 available samples. Of the three responders, two had tissue available and neither had a mutation. Of the three patients who were found to carry mutations, two had stable disease as their best response and one had progressive disease. These findings corroborate the existing data suggesting that, in contrast to the oral tyrosine kinase inhibitors, EGFR mutations do not seem to play a role in predicting response from cetuximab. This is not completely unexpected given the fact that the mutations occur at the ATP-biding site of the EGFR, which is the binding site for the tyrosine kinase inhibitors but not for cetuximab.

Two multi-institutional phase II trials, using similar designs, tested the combination of cetuximab with standard platinum-based doublets in patients with previously untreated advanced NSCLC. The first, led by the University of Colorado investigators, used carboplatin and paclitaxel (7); the second, led by University of Alabama researchers, used carboplatin and gemcitabine (8). All patients had EGFR-positive tumors. The concomitant use of cetuximab with chemotherapy did not seem to enhance overall toxicity. The response and survival results in both trials were encouraging (Table 1) and compared favorably to previous trials using chemotherapy alone.

A European randomized phase II trial compared the efficacy of cisplatin and vinorelbine with or without cetuximab as first-line therapy in patients with advanced NSCLC (9). A total of 86 patients were enrolled (43 per arm). Confirmed objective response rates were noted in 35% of patients treated with cetuximab plus chemotherapy versus 28% of patients in the chemotherapy only arm. Time to progression was nearly identical between the two arms (4.8 versus 4.3 months). In the cetuximab-treated patients, median survival was 8.3 months and 1-year survival was 32%, whereas patients in the reference arm had a median survival of 7.0 months and a 1-year survival of 26%. At 2 years, 14% of patients in the cetuximab arm were still alive but there were no survivors in the control arm.

The four phase III clinical trials that added gefitinib or erlotinib to standard chemotherapy failed to show a survival advantage (10–13). On the other hand, although not yet subjected to phase III testing, the preliminary experience with cetuximab has shown promising results. Thus, it is pertinent to highlight some of the differences between cetuximab and the tyrosine kinase inhibitors that may have implications for their future use in clinical practice.

First, the effect of cetuximab on the ligand binding site of the receptor leads to internalization and subsequent degradation, with no viable receptor left on the cell surface. The tyrosine kinase inhibitors bind to the intracellular tyrosine kinase domain and cause temporary (reversible) inhibition of the receptor. Second, like other antibodies, it is possible that cetuximab stimulates antibody-dependent cell-mediated cytotoxicity, which may contribute to its antitumor effects (14). Third, pharmacologic differences may also play a role. Tyrosine kinase inhibitors are subject to oral absorption, which can vary widely among individuals, and interact directly with cytochrome P450 and other cytochrome systems. Cetuximab is administered i.v. and has a more predictable pharmacokinetic curve. Fourth and lastly, most patients who received cetuximab had some degree of EGFR expression and may have represented a more “targeted” population, in contrast to patients treated with tyrosine kinase inhibitors who were not selected on the basis of EGFR expression. Whether or not EGFR immunohistochemical expression is a predictor of benefit from cetuximab or tyrosine kinase inhibitors remains controversial (15).

Clinical responses to gefitinib after failure to cetuximab have been reported (16). However, perhaps more pertinent is a recent report by investigators at the Dana-Farber Cancer Institute who compared the effects of gefitinib and cetuximab on NSCLC cell lines bearing EGFR mutations (17). For wild-type cell lines, the effects of the two agents on growth inhibition and induction of apoptosis were comparable. However, for cell lines bearing the EGFR mutations, gefitinib was more effective than cetuximab. The investigators supplemented their experiment with clinical data on four patients, all of whom were mutation carriers, who had significant responses to gefitinib after deriving no substantial benefit from cetuximab.

In first-line NSCLC, European investigators are conducting a phase III trial of cisplatin and vinorelbine with or without cetuximab as a follow-up to the randomized phase II results discussed above. U.S. investigators from the Southwest Oncology Group recently completed a randomized phase II study of cetuximab given both concomitantly and after carboplatin and paclitaxel or given only after chemotherapy to address the best sequence of administration of cetuximab and chemotherapy. Investigators from the Eastern Cooperative Oncology Group recently launched a phase II trial of single-agent cetuximab in patients with bronchioloalveolar carcinoma.

In the second-line therapy setting, a four-arm randomized phase III trial is comparing docetaxel and pemetrexed with and without cetuximab. In addition, there are ongoing trials exploring the combination of cetuximab with gefitinib and erlotinib in patients with refractory NSCLC.

As discussed above, a recent phase III trial in patients with locally advanced head and neck cancer showed a significant survival advantage for patients treated with radiation plus cetuximab compared with radiation alone (4). This experience stimulated investigators to explore cetuximab in stage III locally advanced NSCLC. The Radiation Therapy Oncology Group recently completed accrual to a phase II trial of concurrent radiation and carboplatin/paclitaxel/cetuximab followed by two cycles of consolidation with the same triple combination. The Cancer and Leukemia Group B recently activated a randomized phase II trial of radiation plus carboplatin/pemetrexed with or without cetuximab, followed by consolidation with pemetrexed.

Lastly, there are a few initiatives exploring the use of cetuximab in special populations. The Cancer and Leukemia Group B has launched a phase II randomized trial of weekly docetaxel with either cetuximab or bortezomib as first-line therapy for patients with a performance status of 2. Other cooperative groups are developing trials designed to incorporate cetuximab with radiation in poor-prognosis patients with locally advanced disease who are not eligible for more aggressive therapy. Investigators at the Harvard-affiliated institutions are currently testing cetuximab in combination with vinorelbine in elderly patients.

Cetuximab is currently approved by the Food and Drug Administration for refractory colon cancer, alone or with irinotecan, and for locally advanced head and neck cancer, along with radiotherapy. The rationale for testing cetuximab in NSCLC is based on the well-established role of EGFR inhibition in this disease. Preliminary data suggest that cetuximab lends itself to combination with chemotherapy and radiation therapy without excessive toxicity and with promising antitumor activity. Phase III data in first- and second-line NSCLC should become available in the near future. At this time, the data, albeit limited, are sufficient to justify the expectation that cetuximab, used in combination with chemotherapy, may have a different fate than the tyrosine kinase inhibitors in combination with chemotherapy. However, only phase III trials will answer this question definitively.

Further, other issues about the optimal use of cetuximab in NSCLC remain open to debate. What is the best sequence of administration for cetuximab and chemotherapy? Is the best use of cetuximab in combination with radiotherapy? What about combinations with other targeted agents? And, finally, are there surrogate markers or clinical predictors for benefit from cetuximab? These and other questions will hopefully be addressed by the ongoing research.

Dr. Bruce Johnson: In my opinion, a response rate of 4.5% is so low a signal that there is no clear advantage from the randomized phase II studies to say that cetuximab would add a lot to chemotherapy. So I'm surprised the company has invested as much as they have in the combination studies without trying to enrich the population.

Dr. Thomas Lynch: The one thing that persuades me this is not a terrible drug to study further is the fact that, in colorectal cancer, it prolonged survival with chemotherapy. And in head and neck cancer, with radiation, it prolonged survival. We haven't been able to find that with the EGFR tyrosine kinase inhibitors.

Dr. Bruce Johnson: I think head and neck cancer is very different from lung cancer, and colon cancer is very different from lung cancer. We have been down this path before of assuming an agent is going to be better with chemotherapy without a whole lot of data going into it.

Dr. Alan Sandler: If you can't beat the results of a phase III study with a phase II, it is hard to go forward. The randomized phase II maybe only shows that the particular way of giving cisplatin/vinorelbine, with a 7-month median survival, isn't a good one. But that is the study that I find the most troubling.

Dr. Paul Bunn: The hazard ratio in the randomized phase II for survival was actually 0.75, although it is not legitimate in a randomized phase II to do that. But most every drug that has been approved for lung cancer has a hazard rate between 0.7 and 0.8. The ongoing trials Dr. Lilenbaum showed are all reasonable. If I owned the stock and it was my money, would I have done as many of these? No. But there is nothing wrong with any of the ones that were done. I think the Southwest Oncology Group study will give us a lot of information. So this is not going to be a home run, but could it be a single? It could be. But we are going to find out from the trials. The trials are the right trials.

Dr. Sandler: All the phase II studies, I think, were fine. The question is, would you go to phase III based on the phase II studies?

Dr. Bunn: No, you wouldn't. But I think this antibody actually might be better than the new ones. When John Mendelsohn and Gordon Sato were making this antibody, they developed a ton of different antibodies. They looked at immunoglobulins G1, G2, and G3, antibody-dependent cellular cytotoxicity, and growth inhibition, and this one stood out. It is possible that this antibody could be better than the humanized ones.

Dr. Alex Adjei: Actually the possibility of antibody-dependent cellular cytotoxicity, since this is a chimeric antibody, was the topic I wanted to bring up for discussion. There was a randomized phase II trial of the Amgen/Abgenix antibody panitumumab, comparing it to chemotherapy, and there was absolutely no difference. Clearly it is early, but the signals from cetuximab look a bit more interesting than from the purely humanized panitumumab. But it maybe that antibody-dependent cellular cytotoxicity is not important. I don't know if anybody has a clue on that.

Dr. David Johnson: I do think this is a good drug. I think gefitinib is a good drug. But I think we've seen some errors made in the development plans. These dollars might have been spent a great deal more wisely in understanding a little bit more about the issues. Why are we asking whether this drug has antibody-dependent cellular cytotoxicity? That seems to me to be a pretty straightforward question that one could answer. If we intend to make consensus statements as part of this conference, I think we should argue for smarter trials based on more reasonable development plans. I worry this drug will end up never being used in this disease.

Dr. Lynch: One of our ex-presidents of American Society of Clinical Oncology tells us that he thinks the planned trials are good trials that will answer the question of whether or not this drug has activity in lung cancer. Our other ex-president feels that these are not good trials. Where do you disagree and on which trials?

Dr. David Johnson: For each individual trial if you said, “Is this a reasonable thing to do?” The answer is, “Yes, it's a reasonable thing to do.” The development plan is unreasonable, in my view. We don't control that, although we are willing participants, and I think that is part of the problem.

Dr. Bunn: My criticisms would be about the surrogate markers. The data thus far suggest that mutations are not going to be as important for the antibody as they are for the small molecule inhibitors. Again, 90% of the people have wild-type receptors. That's the major problem with mutation: it is only pertinent, at least in North America, to 10% or 12% of the population. But wouldn't we like to know if fluorescence in situ hybridization or immunohistochemistry or something else would enrich populations for this drug? There's not a single paper on any of that. When we get done with all these trials, we are not going to know whether enrichment would help this drug. So that is my major criticism. The Southwest Oncology Group trial has been criticized for not having markers, but a randomized phase II to see whether sequential looks better than combination makes sense.

Dr. David Johnson: I also think the Southwest Oncology Group trial is one that I would do.

Dr. Glenwood Goss: I thought you should have a comment from somebody who is never going to be president of American Society of Clinical Oncology. The phase II studies are not overwhelming, and phase II results are usually better than phase III results. I can tell you that, outside of the United States, an i.v. drug will not be used in non–small-cell lung cancer unless they can define a population which allows a better result than is seen in that randomized phase II study.

Dr. Lilenbaum: I don't disagree with most of the comments. I think that it is very hard to get a signal from those studies, and most people now would say there is not enough to move on to a phase III to study the combination with chemotherapy. I'm intrigued, though, by the cetuximab and radiation data. Few people here would have predicted the difference in survival that was reached in that trial [Proc Am Soc Clin Oncol 2004, abstract 5507]. So I still think that maybe the role for this drug will be locally advanced disease.