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Clinical Cancer Research Vol. 10, 4241S-4244S, June 15, 2004
© 2004 American Association for Cancer Research

Proceedings of the First International Conference

Cetuximab in Advanced Non-Small Cell Lung Cancer

Ramaswamy Govindan

Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 FIRST-LINE THERAPY IN NSCLC
 RECURRENT NSCLC
 FUTURE DIRECTIONS
 OPEN DISCUSSION
 REFERENCES
 
The epidermal growth factor receptor (EGFR) is frequently overexpressed in non-small cell lung cancer (NSCLC). EGFR activation results in phosphorylation of several downstream intracellular substrates involved in cell proliferation, angiogenesis, and inhibition of apoptosis. Cetuximab (C225, Erbitux), a monoclonal antibody directed against ligand binding in the extracellular domain of EGFR, inhibits tumor growth and is synergistic with chemotherapy and radiation. Cetuximab has been studied in combination with chemotherapy in previously untreated metastatic NSCLC. The response rates in preliminary reports range from 29% to 53%. In patients with refractory/recurrent NSCLC, the combination of docetaxel and cetuximab resulted in a promising response rate of 28%, higher than the typical response rates seen with docetaxel monotherapy in this setting. Addition of cetuximab to chemotherapy is generally well tolerated. Molecular mechanisms predicting response to cetuximab therapy are currently not well understood. Studies are ongoing to assess the single-agent activity of cetuximab in metastatic NSCLC.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
FIRST-LINE THERAPY IN NSCLC
 RECURRENT NSCLC
 FUTURE DIRECTIONS
 OPEN DISCUSSION
 REFERENCES
 
Lung cancer is the leading cause of cancer-related mortality in the United States (1) . Non-small cell lung cancer (NSCLC) accounts for >87% of all cases in lung cancer (2) . More than two-thirds of patients with NSCLC present with locally advanced or systemic disease. Systemic chemotherapy has been shown to prolong survival compared with best supportive care in metastatic NSCLC (3) . However, a plateau has been reached with the use of cytotoxic chemotherapy in advanced NSCLC (4) . In the effort to develop more specific and effective therapies, several molecular targets of potential importance have been identified in NSCLC (5) . In particular, the epidermal growth factor receptor (EGFR) is commonly overexpressed in NSCLC, and overexpression of EGFR has been associated with poor prognosis (6, 7, 8) . In preclinical models, EGFR inhibition by monoclonal antibody or by the use of tyrosine kinase inhibitors (TKIs) has been associated with decreased cell proliferation, increased apoptosis, and decreased angiogenesis (9, 10, 11) .

Cetuximab (C225, Erbitux) is a chimeric monoclonal antibody that binds to the extracellular domain of EGFR to block ligand binding, which results in inhibition of autophosphorylation of EGFR (12) . EGFR binding by cetuximab results in cell cycle arrest, increased expression of p27, and increased expression of proapoptotic proteins, including bax, caspase 3, caspase 8, and caspase 9, or decreased expression of antiapoptotic proteins such as bcl-2. In addition, cetuximab has been shown to decrease the production of vascular endothelial growth factor and basic fibroblast growth factor in orthotopic tumor models. Preclinical studies indicated synergism between cetuximab and a number of chemotherapeutic agents, including cisplatin and paclitaxel, in a wide variety of cell lines. Cetuximab appears to be synergistic with radiation treatment as well.

Phase I studies demonstrated nonlinear dose-dependent pharmacokinetics, with saturation of drug elimination occurring at dose levels between 200 and 400 mg/m2. Cetuximab is administered at a loading dose of 400 mg/m2 followed by a maintenance dose of 250 mg/m2 weekly. Cetuximab is well tolerated when administered alone, in combination with chemotherapy, or with radiation treatment. The most common grade 3 or 4 toxicities include asthenia, fever, nausea, and acne. Approximately 4% of patients develop grade 3 or 4 hypersensitivity reaction, and nearly 11% experience grade 3 or 4 acneiform rash (13) .


   FIRST-LINE THERAPY IN NSCLC
Top
 ABSTRACT
 INTRODUCTION
 FIRST-LINE THERAPY IN NSCLC
RECURRENT NSCLC
 FUTURE DIRECTIONS
 OPEN DISCUSSION
 REFERENCES
 
In a Phase I/II study of paclitaxel, carboplatin, and cetuximab, 31 patients with previously untreated metastatic NSCLC were enrolled (14) . The primary objective of the study was to assess toxicity; secondary objectives included assessment of response rates and 1-year survival. Eligible patients received 225 mg/m2 paclitaxel i.v. over 3 h followed by carboplatin administered to attain an area under the curve 5. Chemotherapy cycles were administered every 3 weeks for a maximum of six cycles in the absence of progression or toxicity. Cetuximab was administered with a loading dose of 400 mg/m2 followed by a weekly dose of 250 mg/m2. This combination chemotherapy regimen produced predictable toxicities of myalgia, arthralgia, neutropenia, and rash. The median duration of therapy with cetuximab was 19 weeks, with a promising median survival of 15.7 months [95% confidence interval (CI), 10.2–17.5 months]. The median time to disease progression was 4.5 months (95% CI, 2.8–5.8 months).

In a similarly designed Phase II study, cetuximab was administered along with gemcitabine/carboplatin combination chemotherapy in 35 patients with metastatic NSCLC. The most common grade 3 side effects included rash (20%) and fatigue (14%). Whereas partial response was seen in 29% of patients, an additional 60% of patients had stable disease. The time to disease progression was 165 days (95% CI, 144–188 days), and the 1-year survival rate was 43.8% (15) .

In a randomized Phase II study, patients with metastatic NSCLC received either cisplatin, vinorelbine, and cetuximab or cisplatin and vinorelbine alone (16) . Of the 61 patients enrolled in the study, the 36 patients assigned to receive cetuximab and chemotherapy had a higher response rate (53%; 95% CI, 36.1–69.8) than those who received chemotherapy alone (26%; 95% CI,18.6–49.9). The disease control rate was 93% in the cetuximab group compared with 77% in the chemotherapy only group. The time to progression and survival data are not yet available. The higher response rates and disease control rates seen with the addition of cetuximab in this randomized Phase II study certainly warrant additional studies.

Tables 1Citation and 2Citation summarize the toxicity and efficacy reported in the randomized studies. These three preliminary studies demonstrate the feasibility of combining cetuximab with platinum-containing chemotherapy regimens. Whereas these studies are encouraging, only large prospective randomized studies can help define whether concurrent administration of cetuximab and chemotherapy will improve survival compared with chemotherapy alone.


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  		Table 1 Cetuximab with cytotoxic chemotherapy

 

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  		Table 2 Comparison of docetaxel with cetuximab (75 mg/m2) with prior Phase III studies with docetaxel alone

 

   RECURRENT NSCLC
Top
 ABSTRACT
 INTRODUCTION
 FIRST-LINE THERAPY IN NSCLC
 RECURRENT NSCLC
FUTURE DIRECTIONS
 OPEN DISCUSSION
 REFERENCES
 
Docetaxel is approved for use in the United States for the treatment of patients with relapsed NSCLC (17 , 18) . However, the reported response rates with docetaxel in three large Phase III studies ranged from 7.8% to 8.9%, and the median time to disease progression was approximately 2.9 months. In a Phase II study led by investigators at the M. D. Anderson Cancer Center, cetuximab was administered concurrently with docetaxel (19) . Only patients who progressed while receiving platinum-based therapy or within 3 months of completing a platinum-based regimen were eligible. In this prospective study, 75 mg/m2 docetaxel was administered i.v. every 3 weeks concurrently with cetuximab initially given at a loading dose of 400 mg/m2 followed by a maintenance dose of 250 mg/m2. The response rate was 28%, including one patient who achieved a complete response. Nearly 66% of patients had stable disease with this combination regimen. Considering that this study population represents patients who have disease refractory to platinum-based therapy, these responses seem very encouraging.


   FUTURE DIRECTIONS
Top
 ABSTRACT
 INTRODUCTION
 FIRST-LINE THERAPY IN NSCLC
 RECURRENT NSCLC
 FUTURE DIRECTIONS
OPEN DISCUSSION
 REFERENCES
 
Several questions remain unanswered with regard to the role of cetuximab in patients with NSCLC. What is the activity of single-agent cetuximab in NSCLC? Is there a role for cetuximab in combination with cytotoxic chemotherapy? What are the optimal dose and sequence of cetuximab in combination with chemotherapy? Will addition of cetuximab to radiation therapy improve the outcome of patients with locally advanced NSCLC?

The addition of gefitinib, an oral EGFR-selective TKI, to systemic chemotherapy did not result in any additional benefit over chemotherapy alone (20) . This disappointing result has led some to rethink the strategy of combining cytotoxic chemotherapy combinations with targeted agents. However, it is worth keeping in mind that the addition of trastuzumab, a specific inhibitor of Her2/neu, closely related to EGFR, did prolong survival when added to chemotherapy in patients with metastatic breast cancer (21) . Whether a EGFR-specific antibody such as cetuximab will be more synergistic with chemotherapy than EGFR TKIs is unknown.

An ongoing study is evaluating the single activity of cetuximab in patients with NSCLC who have failed one platinum-containing therapy. Two cohorts of the patients will be enrolled in this study: one with no EGFR staining in the tumor; and another subset with EGFR expression. The primary objective of the study is to define the response rate of single-agent cetuximab.

There appears to be up-regulation of EGFR in tumors after radiation therapy, presumably producing the increased cell proliferation and cell survival associated with EGFR up-regulation. Because EGFR inhibitors are synergistic with radiation therapy, the Radiation Therapy Oncology Group is planning to conduct a Phase II study of cetuximab added to a paclitaxel/carboplatin/radiation therapy regimen. The primary end point of this study is 3-year survival. In a prospective study conducted by the Eastern Cooperative Oncology Group, hyperfractionated accelerated radiation therapy produced a median survival of 20 months in patients with stage III NSCLC compared with 13 months in a historical control (22) . Based on these encouraging results, the Eastern Cooperative Oncology Group plans to conduct a Phase II study in which cetuximab will be given concurrently with hyperfractionated accelerated radiation therapy in patients with locally advanced NSCLC.

Finally, preclinical evidence suggests that a combination of inhibition of EGFR and inhibition of vascular endothelial growth factor is beneficial (23, 24, 25, 26) . Whether such inhibition of dual pathways would lead to better outcomes remains to be determined.

In summary, cetuximab has shown some promising results in advanced NSCLC. It is hoped that ongoing studies will identify the appropriate role for this agent in the management of patients with NSCLC.


   OPEN DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 FIRST-LINE THERAPY IN NSCLC
 RECURRENT NSCLC
 FUTURE DIRECTIONS
 OPEN DISCUSSION
REFERENCES
 
Dr. Thomas Lynch: I have been very impressed about the issue of interaction with chemotherapy possibly being distinctly different with this compound than it is with the oral TKIs. What do people think about this issue of chemotherapy interaction with cetuximab?

Dr. Roman Perez-Soler: The randomized Phase II trial in NSCLC showed a 20% difference in response rate, and the Eastern Cooperative Oncology Group Phase III randomized study in head and neck cancer showed a 9% versus 22% difference in response rate. I am inclined to think that the antibodies are different from the small molecule TKIs. The preclinical data suggested similar additive effects for both, but it seems that the clinic confirms the preclinical data for the antibodies only. The only explanation that I can see is that the antibodies destroy the receptor by internalization, whereas the small molecule drug just inhibits temporarily or reversibly. I think that the emerging data suggest that the antibodies synergize better with chemotherapy.

Dr. Paul Bunn: Merck is going to do a randomized Phase III trial of chemotherapy with or without cetuximab in patients with advanced, untreated NSCLC in Europe. This study should answer the question. You can certainly debate whether it is worth doing that Phase III trial, given the data from all four trials with chemotherapy combinations ± small molecule TKIs (gefitinib and erlotinib). In all of these negative trials, the gemcitabine/cisplatin and carboplatin/paclitaxel combinations showed a median time to progression of 4 months, a response rate in the mid-20s and median survivals of 8 months, which is identical to what chemotherapy alone does. So, if you were looking for a signal in those to move on from those trials, there was no signal. Now, you can debate whether there is a signal in those cetuximab trials that Dr. Govindan showed. Both of the two front-line trials of cetuximab plus chemotherapy had longer time to progression and longer survival than the big randomized trials. Does that mean you should do a randomized trial? If there is difference, a major difference, it is probably that there might be an immune response to a tumor cell that has an antibody sticking on its receptor, and whether that accounts for the difference is probably a testable hypothesis.

Dr. Eric Rowinsky: There are Phase II trials. There are gefitinib trials with docetaxel. There are gefitinib trials with paclitaxel/carboplatin that showed pretty nice activity in single-institution trials. There is enough reason for the INTACT and the TRIBUTE Phase III trials to fail, irrespective of the combination, because of the dilution with the heterogeneity, the fact that the patients who are going to respond are the survivors who are funneled through the system. I think that Dr. Perez-Soler is right about the internalization of receptor by the antibody, but the magnitudes of cytotoxicity, the G1 arrest, are the same with small molecules and the antibody. As far as pulses are concerned, you do not get pulses with the antibody; the antibody remains in the system for long periods of time, and you get continuous suppression. So, I would not condemn the small molecules and combinations until we do some definitive trials in the right populations.

Dr. Lynch: We have talked about whether or not, with a drug like erlotinib or gefitinib or cetuximab, we should be looking at a biologically active dose, or we should be looking at the MTD, and I think that Dr. Perez-Soler showed a very nice distinction between those two comments. Should we be pushing dose? Is dose something that people think is not being addressed sufficiently in these trials?

Dr. Alex Adjei: I think that the big question is if we know the biologically active dose. For a number of these agents, you do not really have a marker before it gets to Phase II. You may be able to show that you inhibit some protein, but it is not correlating with the clinical responses. So, you get concerned about using that dose, not knowing for sure whether you really have a biologic dose. One of the things that we forget is the pharmacology of these drugs. A lot of these small molecules tend to be substrate for cytochrome P-450 3A4, 3A5, they tend to be substrate for multidrug-resistant protein. So, the exposure is radically different for different patients, and we really do not know the true biological dose. Apart from things like grapefruit juice, there are many drugs that are either inhibitors or activators of 3A4. There are so many that you cannot really exclude them in trials. So, there are real exposure issues, and although the biology might be the same, you do not get reproducible dosing.

Dr. David Gandara: There is a small subset of patients who get gefitinib, maybe 3%, who have marked liver function abnormalities. We think that may be the single-nucleotide polymorphisms that are involved with gefitinib in those patients, and we are trying to collect blood or genomic DNA to see if that is the case.

Dr. Lynch: We heard the results of Karen Kelly’s trial that showed a median survival with cetuximab of 15.7 months. Now, that median survival was enough to generate a Phase III trial of the Isis compound and of bevacizumab. We all think now that bevacizumab is justified because we have seen the colorectal data, but before that, we were basing it on a median survival of 15.7 months in a randomized Phase II trial. I would be interested in Dr. Schiller’s thoughts. You were the first person to have a 15.7-month median survival, and you went ahead to a randomized Phase III trial.

Dr. Joan Schiller: You have not seen it published, have you? The randomized trial was negative. I felt very confident about our Phase II data, and yet clearly the result was not generalizable to the general patient population.

Dr. Lynch: Dr. Socinski, earlier you said that you would be impressed with a 12-month median survival.

Dr. Mark Socinski: With the caveat of knowing who the patients were. For cetuximab, the Gatzemeier data are convincing on the response rate end point. With the Kelley data, the median survival is nice, but the time to progression, as Dr. Govindan pointed out, is still 4–4.5 months.

Dr. Bruce Johnson: We have lots and lots of Phase II studies that have 10- or 11-month median survival, so finding median survival rates of 16 months in Phase II is certainly good. Although, as Dr. Schiller and others have found, having a median survival of 14–16 months in a Phase II does not guarantee success, the converse is that there is only one example of a 10-month survival in Phase II going on to a positive Phase III in all the Phase III lung cancer trials done in North America in the last 25 years. We published that analysis in Journal of the National Cancer Institute a couple of years ago (27) . Statistically, if you analyze it historically, a long survival in the Phase II will double or triple the chances of having a positive in a randomized Phase III. So, it is not as though the information is useless.


   FOOTNOTES
 
Presented at the First International Conference on Novel Agents in the Treatment of Lung Cancer, October 17–18, 2003, Cambridge, Massachusetts.

Requests for reprints: Ramaswamy Govindan, Division of Medical Oncology, Washington University School of Medicine, 4960 Children’s Place, Box 8056, St. Louis, MO 63110. Phone: (314) 362-4819; Fax: (314) 362-7086; rgovinda{at}im.wustl.edu


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 FIRST-LINE THERAPY IN NSCLC
 RECURRENT NSCLC
 FUTURE DIRECTIONS
 OPEN DISCUSSION
 REFERENCES
 

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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
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Annual Meeting Education Book Meeting Abstracts Online