Journal of Clinical Oncology, Vol 22, No 16 (August 15), 2004: pp. 3238-3247
© 2004 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.11.057
Determinants of Tumor Response and Survival With Erlotinib in Patients With Non—Small-Cell Lung Cancer
Román Pérez-Soler,
Abraham Chachoua,
Lisa A. Hammond,
Eric K. Rowinsky,
Mark Huberman,
Daniel Karp,
James Rigas,
Gary M. Clark,
Pedro Santabárbara,
Philip Bonomi
From the Montefiore Medical Center/Albert Einstein College of Medicine, Bronx; New York University School of Medicine, New York, NY; Institute for Drug Development, San Antonio, TX; Beth Israel Deaconess Medical Center and Deaconess Medical Center, Boston, MA; Dartmouth-Hitchcock Medical Center, Lebanon, NH; OSI Pharmaceuticals Inc, Boulder, CO; and Rush Cancer Institute, Chicago, IL
Address reprint requests to Román Pérez-Soler, MD, Department of Oncology, Hofheimer 100, Montefiore Medical Center/Albert Einstein College of Medicine, 111 E 210th St, Bronx, NY 10467; e-mail: rperezso{at}montefiore.org
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ABSTRACT
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PURPOSE: Erlotinib is a highly specific epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. This phase II study of erlotinib in patients with HER1/EGFR-expressing non–small-cell lung cancer previously treated with platinum-based chemotherapy evaluated tumor response, survival, and symptom improvement.
PATIENTS AND METHODS: Fifty-seven patients received an oral, continuous daily dose of 150 mg of erlotinib. Assessments of objective response used WHO and Response Evaluation Criteria in Solid Tumors criteria. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, supplemented with a lung cancer module, Quality of Life Questionnaire LC13, was used to measure health-related quality of life. Additional analyses were performed to identify predictors of response and survival.
RESULTS: The objective response rate was 12.3% (95% CI, 5.1% to 23.7%). Responses were observed regardless of type or number of prior chemotherapy regimens. Median survival time was 8.4 months (95% CI, 4.8 to 13.9 months), and the 1-year survival rate was 40% (95% CI, 28% to 54%). Erlotinib therapy was associated with tumor-related symptom improvement. The drug was well tolerated; drug-related cutaneous rash and diarrhea were observed in 75% and 56% of patients, respectively. One patient experienced toxicity consisting of severe grade 3 rash and diarrhea. Time since diagnosis and good performance status were significant predictors of survival in a multivariate Cox proportional hazards model, whereas HER1/EGFR staining intensity was not. Additionally, survival correlated with the occurrence and severity of rash.
CONCLUSION: Erlotinib was active and well tolerated in this patient population, and further clinical development is clearly warranted. Cutaneous rash seems to be a surrogate marker of clinical benefit, but this finding should be confirmed in ongoing and future studies.
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INTRODUCTION
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Several human malignancies are associated with aberrant or overexpressed epidermal growth factor receptor (HER1/EGFR).1-3 HER1/EGFR tyrosine kinase serves as a potential target for therapeutic intervention in human tumors including ovarian, head and neck, breast, bladder, lung, and other squamous cell carcinomas.4-7 Overexpression of HER1/EGFR has been directly related to chemoresistance and poor prognosis.8-10 Several studies have shown that HER1/EGFR expression or overexpression is common in non–small-cell lung cancer (NSCLC) tumor samples.9-17
Erlotinib (Tarceva; OSI-774; OSI Pharmaceuticals, Melville, NY) is a potent and selective inhibitor of HER1/EGFR tyrosine kinase. It is a direct and reversible enzyme inhibitor in vitro, with a median inhibitory concentration of 2 nmol/L (0.79 ng/mL). Erlotinib reduces HER1/EGFR autophosphorylation in intact tumor cells with a median inhibitory concentration of 20 nmol/L (7.9 ng/mL), inhibits epidermal growth factor-dependent cell proliferation at nanomolar concentrations, and blocks cell-cycle progression at the G1 phase.18
Oral administration of erlotinib to mice reduced the level of HER1/EGFR autophosphorylation in human tumor xenografts by over 70% for more than 12 hours. Daily administration markedly inhibited the growth of HN5 human head and neck tumor and A431 squamous cell carcinoma xenografts in athymic mice, with near complete inhibition of tumor growth during a 20-day treatment regimen at the highest doses.19
In two phase I erlotinib dose-escalation studies in patients with advanced solid malignancies,20 14 patients achieved stable disease. The most common adverse events were diarrhea and rash, regardless of dose and schedule. Diarrhea was considered the dose-limiting adverse event. The maximum-tolerated dose and recommended phase II dose was 150 mg once daily on a continuous dosing schedule.
Results from pharmacokinetic studies showed that erlotinib is highly protein bound in humans (92% to 95%). The primary route of metabolism is oxidation by the hepatic cytochromes CYP3A4 and CYP3A5 and the pulmonary cytochrome CYP1A1. A potential for drug-drug interaction exists when erlotinib is coadministered with drugs that are highly protein bound or are CYP3A4 inhibitors or inducers.
The high frequency of overexpression of HER1/EGFR in NSCLC provides a scientific rationale for evaluating the therapeutic effect of erlotinib in this tumor type. In addition, there is a clear need for new therapeutics to treat patients with NSCLC, especially those patients with advanced disease who have a poor prognosis after failure of platinum-based chemotherapy. The majority of these patients will not benefit from additional chemotherapy, including taxane regimens. The current study was planned to estimate the objective tumor response rate of erlotinib administered as a single agent to patients with advanced (stage IIIB or IV) or recurrent metastatic HER1/EGFR-positive NSCLC who were previously treated with platinum-based combination chemotherapy. Secondary objectives were to estimate the stable disease rate, duration of response, time to disease progression, overall and 1-year survival, health-related quality-of-life (HRQOL) outcomes, and safety profile of erlotinib in this population.
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PATIENTS AND METHODS
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Eligibility Criteria
The study population included male and female patients 18 years of age or older. The main criteria for inclusion were documented stage IIIB or IV advanced or recurrent metastatic NSCLC, disease progression or relapse after platinum-based therapy, measurable disease, and documentation of HER1/EGFR positivity. Additional criteria included Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and adequate bone marrow, hepatic, and renal function (total bilirubin and creatinine  1.5 x the upper limit of normal). Patients with brain metastases were eligible if they were clinically stable for at least 8 weeks.
Procedures Performed at Screening
The procedures performed at screening included a complete medical and surgical history, standard laboratory studies, ECG, pregnancy test with a negative result, tumor assessment, determination of HER1/EGFR status by immunohistochemistry in a tumor specimen conducted by a central laboratory (IMPATH, Los Angeles, CA), with HER1/EGFR positivity defined as more than 10% of cells staining positive, and administration of an HRQOL questionnaire. All patients gave written informed consent in accordance with policies of local human subjects committees before screening and initiation of therapy.
Procedures Performed During the Study
Procedures that were to be completed at weeks 2, 4, 6, and 8, every 4 weeks throughout the study, and at the time of study discontinuation included an interval history and reassessment of performance status, brief physical and skin examination, weight, and vital signs, complete blood count with differential and platelet count, blood biochemistry, and urinalysis. Ophthalmologic evaluations were to be repeated after 4 weeks of erlotinib therapy, within 2 weeks after any dose escalation, and at the time of study discontinuation only if a change from baseline had been detected with subsequent examinations.
Treatment Plan
Patients received erlotinib at an initial dose of 150 mg in a tablet formulation supplied by the sponsor (OSI Pharmaceuticals) that was self-administered orally once daily on a continuous basis. The dose was taken in the morning with up to 200 mL of water. The dose could be increased to 200 mg/d in patients who had received at least 4 weeks of continuous dosing at 150 mg/d and did not experience any drug-related adverse events during the previous 4-week cycle. The dosage was to be decreased in 25- or 50-mg decrements if the patient experienced drug-related ocular toxicities of any National Cancer Institute Common Toxicity Criteria grade, had any drug-related adverse events subjectively considered intolerable, had any Common Toxicity Criteria  grade 3 drug-related adverse events not controlled with optimal supportive medication, or had undergone dose reduction for a drug-related adverse event that did not improve by at least one grade level to less than grade 3 within 2 weeks. Therapy could be continued after dose reduction to the minimum daily dose of 25 mg despite drug-related toxicity if the investigators and sponsor felt it was in the patient’s interest.
Erlotinib treatment was planned for a minimum of 8 weeks and was to continue for a maximum of 52 weeks unless disease progression or unmanageable toxicity occurred. Patients with stable or responding disease for whom additional therapy beyond 52 weeks was deemed to be of potential benefit could continue erlotinib.
Tumor Measurements
Measurements of disease sites by clinical examination and radiographic imaging studies (x-ray, computed tomography scan, and magnetic resonance imaging) were collected at baseline before erlotinib therapy. The same methods were used every 8 weeks during the study to assess response. If a patient achieved a complete or partial response, tumor measurements were repeated 4 weeks later to confirm the response.
HRQOL
HRQOL was measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, version 3.0.21 An additional lung cancer module, Quality of Life Questionnaire LC13, was used and is composed of 13 items; it is intended for use among a wide range of lung cancer patients varying in disease stage and treatment modality. Four additional questions were added to assess the effect of any rash, skin pain, and itching, and their impact on daily activities. These four questions were combined into a single rash score.
The HRQOL questionnaire was administered at baseline, every 2 weeks during the first 2 months and monthly thereafter, at the end of study, and at the 1-month and 3-month follow-up visits. The questionnaire was to be completed during office visits before any other evaluations or assessment of adverse events. Changes in HRQOL scores during the study were compared with the baseline score.
Criteria for Evaluation of Efficacy
The primary efficacy variable was the overall response rate, which was defined as the percentage of patients with complete or partial responses. Responses were determined by the investigators according to WHO criteria.22
Evaluation of the objective tumor response was performed every 8 weeks during treatment. Stable disease, duration of overall response, time to progression, and survival were assessed at 2-week intervals for the first 2 months, every 4 weeks until study discontinuation, and at 1-month and 3-monthly intervals after treatment. Patients who met the criteria for complete or partial response had their response confirmed at least 4 weeks after the first determination of response. In addition, responses were also evaluated by the sponsor (OSI Pharmaceuticals) according to Response Evaluation Criteria in Solid Tumor (RECIST) criteria.23
Statistical Analysis
This was a single-arm, open-label, multicenter phase II study. A Gehan two-stage design was used to determine sample size.24 It was anticipated that a total of 37 patients would be enrolled to ensure that 33 patients would be fully assessable for response. With 33 patients, the response rate of interest (10%) would be estimated with a maximum SE of 9%. A total of 57 patients were accrued to compensate for patients who had early progression and/or death before completing 8 weeks of study therapy. All 57 patients were included in all efficacy and safety analyses. The parameters of interest were estimated and presented with their 95% CIs using exact methods. All time-to-event variables, including duration of response and progression-free and overall survival, were analyzed using Kaplan-Meier product-limit survival estimates. Pretreatment characteristics were analyzed in univariate and multivariate logistic regression models for their ability to predict objective response and in univariate and multivariate Cox proportional hazards models for their ability to predict survival. Multivariate models were constructed using stepwise variable selection techniques. Changes in HRQOL from baseline, including impact of disease-related symptoms and rash, were evaluated using paired t tests. All analyses were performed using SAS/STAT User’s Guide version 8.2 for Windows (SAS Institute, Cary, NC).
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RESULTS
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A total of 84 patients were screened for the study; 57 were enrolled and treated with erlotinib. The most common reasons that screened patients were not enrolled onto the study were HER1/EGFR status (eight patients were negative, one was too weak, and five had no tissue specimens available) and rapid deterioration (four patients). The 57 patients were accrued from January 25, 2000, until February 14, 2001. All patients were assessable for tumor response and toxicity. Table 1 shows the characteristics of the patient population. The median age was 62 years (range, 31 to 83 years), and the majority of patients (63%) had been diagnosed with NSCLC more than 12 months before study enrollment. The median time from initial diagnosis to study entry was 17.7 months (range, 4 to 137 months). The advanced stage of disease in these patients was characterized by multiple sites of distant metastases and the presence of lung cancer signs and symptoms at baseline. Fifty-four patients (95%) reported symptoms at baseline, including fatigue (67%), dyspnea (61%), and cough (60%).
Before study entry, the patients had received various therapies (Table 2). Eighty-two percent of patients had received two or more chemotherapy regimens. Fifteen patients (26%) had received prior docetaxel. All but two patients had been treated with at least one platinum-based combination chemotherapy regimen. One of the two patients who had not received platinum therapy had been treated with gemcitabine-based combinations, and the other patient had been treated with two regimens of paclitaxel. The majority of patients (44 of 57 patients, 77%) had documented disease progression during or within 6 months of their last chemotherapy regimen.
Tumor Response and Survival
Table 3 lists the antitumor response data. Two patients achieved a complete response, and five had a partial response, as determined by both WHO and RECIST criteria. The objective response rate (complete + partial response) was 12.3% (95% CI, 5.1% to 23.7%). On the basis of RECIST criteria, 22 patients (39%) had stable disease and 28 patients (49%) had disease progression as their best tumor response. The number of prior chemotherapy regimens had no effect on response rates (12.8% for patients with two or more prior chemotherapy regimens v 12.3% for the whole group). One of the seven responders had not received prior platinum therapy; this 83-year-old patient, who had pre-existing neuropathy contraindicating platinum therapy, had previously received two gemcitabine-based combinations, one of which included docetaxel. Of the 15 patients previously treated with docetaxel, four (27%) achieved complete or partial responses, and an additional five (33%) had stable disease. Of the 44 patients with documented disease progression within 6 months of their last chemotherapy treatment, three (7%) subsequently achieved a partial response with erlotinib, and 16 (36%) had stable disease.
Thirty-five patients enrolled had adenocarcinoma, four of whom responded to therapy (11.4%; one complete and three partial responses). Of the remaining 22 patients, 11 had large-cell carcinoma, nine had squamous cell carcinoma, and two were not specified; three patients responded to therapy (13.6%), two with large-cell carcinoma (one complete and one partial response) and one with squamous cell carcinoma (partial response). Four of the seven responding patients had adenocarcinoma (one complete response and three partial responses). Histologies were not further classified by subtype; specifically, BAC or BAC-like features were not characterized.
The median duration of response was 19.7 weeks (range, 11.7 to 80.3 weeks). Progression-free survival was measured from the first erlotinib administration to the date of disease progression, start of subsequent anticancer treatment, death, or date of last contact, whichever occurred first. With five patients censored in the analysis, the median progression-free survival time was 9 weeks (95% CI, 8 to 15 weeks). With nine patients still alive and censored in the analysis, the median overall survival time was 8.4 months (95% CI, 4.8 to 13.9 months), and the 1-year survival rate was 40% (95% CI, 28% to 54%; Fig 1).
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Fig 1. Overall survival of patients treated with erlotinib. Bullets represent patients still alive at time of analysis.
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Determinants of Tumor Response and Survival
Several pretreatment characteristics were analyzed in univariate and multivariate logistic regression models for their ability to predict the objective response rate. Table 4 shows the results of these analyses. Time from last chemotherapy was the only pretreatment characteristic that significantly predicted the objective response rate in the multivariate analysis (P = .033), although time since initial diagnosis was marginally predictive (P = .086).
The same pretreatment characteristics were analyzed in univariate and multivariate Cox proportional hazards models for their ability to predict survival (Table 5). Time since initial diagnosis and ECOG performance status were the only pretreatment characteristics that predicted survival in the multivariate model.
Patients previously treated with docetaxel as second-line therapy had a higher objective response rate compared with the entire group (26.7% v 12.3% overall, respectively), a similar median survival time of 8.6 months (95% CI, 2.2 to 20.8 months), and a 1-year survival rate of 47% (95% CI, 21.3% to 73.4%).
Exploratory analyses were conducted to investigate any potential relationship between rash and clinical outcomes. For these analyses, rash was defined as MedDRA (Medical Dictionary for Regulatory Activities, version 5.0; MedDRA MSSO, Reston, VA) codes that contain the terms rash, dermatitis, or acne. Rash was experienced by all seven patients who had an objective response and by 21 (95%) of 22 patients who had stable disease, but only 15 (54%) of 28 patients (54%) who had progressive disease experienced rash (data not shown). Thus, rash was necessary but was not a sufficient condition for tumor response in this study.
In addition, patients who experienced rash had significantly longer survival (Fig 2). The median survival of patients without rash was 1.5 months compared with 8.5 and 19.6 months for patients with a maximum of grade 1 rash and grade 2 or 3 rash (only one patient experienced grade 3 rash), respectively. All pair-wise comparisons were statistically significant. When rash was included in the multivariate analysis along with the factors listed in Table 5, rash was the most significant predictor of survival, with hazard ratios of 0.13 (95% CI, 0.06 to 0.30) and 0.05 (95% CI, 0.02 to 0.15) for grade 1 and grade 2 or 3 rash, respectively (P < .0001 for each factor; Table 6).
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Fig 2. Survival of patients by grade of rash. Bullets represent patients (Pts) still alive at time of analysis.
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The median time to the first occurrence of rash, regardless of severity, was 10 days (range, 2 to 44 days), whereas the median duration of erlotinib exposure was 9 weeks (range, 2 to 131 weeks). Therefore, it is unlikely that the relationship between rash and increased survival can be explained simply by longer exposure to erlotinib. However, to investigate this possibility, we performed an additional multivariate analysis in which rash, regardless of severity, was included as a time-dependent variable, and cumulative dose of erlotinib was included along with all of the factors in Table 5. Rash continued to be a significant predictor of survival, with a hazard ratio of 0.24 (95% CI, 0.10 to 0.56; data not shown).
Symptom Improvement and HRQOL
The HRQOL questionnaires showed that patients in this study had multiple lung cancer–related symptoms and relatively good functional status, which was consistent with a European Organization for Research and Treatment of Cancer reference population with recurrent or metastatic NSCLC. The overall incidence of fatigue, dyspnea, and cough, which were the most frequent signs and symptoms captured by the HRQOL, decreased from 67%, 61%, and 60% at baseline to 49%, 37%, and 39%, respectively, after initiation of erlotinib therapy (data not shown).
Although the results must be treated cautiously because the P values were not corrected for the large number of comparisons, some significant (P < .05) changes were seen. Pain was reduced at 2 weeks of therapy, and emotional functioning was increased during the first 4 weeks of therapy, but both subsequently returned to baseline levels. Diarrhea and sore mouth were reported as increased from baseline while on therapy.
Further analysis of the HRQOL scales suggested that responders sustained their quality of life longer than nonresponders, but few comparisons reached statistical significance. These relationships may serve as a historical comparison for future randomized studies.
Adverse Events
All 57 patients received at least one dose of erlotinib and were analyzed for safety. The majority of patients received the 150 mg/d target dose. Five patients (9%) discontinued erlotinib as a result of an adverse event or withdrawal of consent, and two additional patients (4%) required dose reduction because of an adverse event after receiving multiple cycles at 150 mg. The median duration of erlotinib exposure was 9 weeks (range, 2 to >131 weeks).
Table 7 lists the most common drug-related adverse events. Fifty-six patients (98%) had at least one drug-related adverse event, 38 patients (67%) had drug-related adverse events with a maximum severity of grade 1 or 2, and 17 patients (30%) had at least one grade 3 drug-related adverse event. Less than 10% of patients showed signs of ocular toxicity attributable to erlotinib therapy; no incidence exceeded grade 2. Dysphagia, pruritus, fatigue, dyspnea, decreased appetite, and anxiety were the only drug-related grade 3 events reported in two patients, and none was reported in more than two patients (4%). Interstitial pneumonia and grade 4 events were not reported.
The incidence of drug-related rash and diarrhea during the study was of special interest. Rash, not otherwise specified, was experienced by 67% of patients. When the definition was expanded to include dermatitis and acne, the incidence increased to 75% (43 of 57 patients). Rash and/or diarrhea occurred as single events or concurrently in 89% of patients. Three patients (5%) experienced grade 3 dermatologic events (one rash and two pruritus without associated rash). Only one patient had grade 3 diarrhea (also with grade 3 rash). Grade 4 rash or diarrhea was not noted. The median time to the first occurrence of rash, regardless of severity, was 10 days (range, 2 to 44 days). The median time to the first occurrence of diarrhea, regardless of severity, was 14 days (range, 1 to 420 days).
Three patients (5%) discontinued therapy because of adverse events. Only one withdrawal was considered related to erlotinib (grade 2 nausea and vomiting). A total of 20 patients (35%) died during treatment or within 30 days of the last dose of erlotinib. These deaths were a result of disease progression (85%) or respiratory events attributed to underlying disease (15%); none was a result of pneumonitis or attributed to erlotinib. At the last follow-up, nine patients (16%) were still alive, and two patients remained on erlotinib therapy.
Changes in laboratory parameters, vital signs, and physical examination data observed were not deemed clinically significant. Sporadic hematologic and clinical chemistry abnormalities were more often caused by the underlying condition or intercurrent illnesses than to erlotinib therapy. These data show that erlotinib is not associated with notable myelotoxicity, even in patients with extensive prior chemotherapy. Hepatic abnormalities were relatively mild (grades 1 or 2), even in patients with elevated liver function results at baseline.
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DISCUSSION
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The 12.3% objective response rate seen in this study exceeded the target level for activity (10%) planned in the protocol. The overall survival of 8.4 months was encouraging when compared with other studies in similar heavily pretreated patient populations. The activity of erlotinib compares favorably with that of docetaxel in less heavily pretreated patients in phase II25 and phase III studies.26,27 Erlotinib has a favorable safety profile, with rash and diarrhea being the most common side effects. Toxicities classically reported with chemotherapy were not noted in this trial. No drug-related deaths occurred, and only one patient withdrew because of drug-related toxicity.
The response rate, although modest, indicates that some NSCLC tumors are dependent on the HER1/EGFR pathway for growth and survival. This is surprising because previous evidence suggests that changes in the HER1/EGFR pathway, although overexpressed in many lung tumors, may not play a major role in the carcinogenesis of lung cancer.28 Moreover, the HER1/EGFR gene product is overexpressed by just two- to three-fold in many NSCLC tumors29 or endogenously activated as a result of mutation in approximately only 16% of NSCLC tumors.30 Ninety percent of the screened patients with tissue specimens available for analysis had tumors expressing HER1/EGFR.
In the preclinical studies with erlotinib, overt tumor regression was observed only in xenografts expressing higher levels of HER1/EGFR than commonly seen in human NSCLC tumors.19 However, the most common drug effect in the cell lines and xenografts studied was tumor growth inhibition. Consistent with this observation, a substantial proportion of patients in this study (39%) experienced disease stabilization. The lack of correlation between HER1/EGFR expression and survival is surprising but may be due to the fact that patients were preselected for HER1/EGFR positivity or that the number of patients was small. It is also possible that a certain level of positivity is required and that any additional positivity does not confer a higher probability of response.
Cutaneous rash, but not diarrhea, was clearly associated with objective response and stable disease and with prolonged survival. This has also been observed in phase II studies of erlotinib in head and neck cancer and ovarian carcinoma.31 Moreover, studies with several different HER1/EGFR-targeted agents show a correlation between rash and clinical efficacy, supporting the role of rash as a surrogate marker of activity. Studies with cetuximab in patients with colorectal cancer (two studies), head and neck cancer (one study), and pancreatic cancer (one study) show that rash correlates significantly with survival.32 Rash has also been associated with survival in a study of gefitinib in patients with head and neck cancer33 and response with ABX-EGF in patients with renal cell carcinoma.34 The possibility that cutaneous tissue damage induced by erlotinib blockade may be a surrogate marker for tumor damage is potentially of clinical importance and needs to be confirmed in future studies.
The correlation between rash and clinical activity could differentiate erlotinib and gefitinib. In the recent reports of the two phase II studies of gefitinib in NSCLC (IDEAL 1 and 2),35,36 data regarding the possible relationship between skin toxicity and survival were not presented. However, in IDEAL 2, all responders had some form of skin toxicity. Updated data from these trials regarding this potentially important issue are needed and eagerly awaited.
The relationship between rash, erlotinib dose, and response has not been fully elucidated. Some preclinical dose-response data suggest that erlotinib should be dosed at the maximum-tolerated dose rather than at a biologically active dose. The occurrence of rash may depend exclusively on effective and prolonged skin HER1/EGFR blockade. However, this is unlikely because, at the recommended erlotinib dose (150 mg/d, the maximum-tolerated dose), the target is probably inhibited in most patients, but only about two thirds develop skin toxicity. Moreover, if there were a positive correlation between tissue damage in the skin and tumor (as a result of receptor inhibition), we would expect the susceptibility to apoptotic cell death or inflammatory response to HER1/EGFR blockade to be controlled by the same genetic determinants (target related or immunologic) in both tissues. Molecular analysis of skin and tumor tissue samples collected before and after therapy as part of an ongoing ECOG phase II study of single-agent erlotinib in patients with NSCLC will hopefully provide answers to some of these questions. An alternative explanation is that although skin rash may require effective target inhibition, it occurs primarily as a result of the patient’s ability to mount an immune-mediated inflammatory response. Thus, rash may be a surrogate of immunocompetence rather than receptor inhibition.
A good performance status, a longer time from diagnosis, and the occurrence of rash were identified as factors predicting favorable clinical outcomes. Performance status is widely recognized as an important prognostic factor in patients with NSCLC.37,38 Time from initial diagnosis has not been previously recognized as a prognostic factor in this patient population, and this observation needs to be validated. However, it suggests that tumors with a more indolent biology may be more sensitive to HER1/EGFR inhibition.
One important observation is that response to erlotinib and survival were independent of the number of prior therapies. Most lung cancers eventually develop pan-resistance to cytotoxic therapy. In in vitro cell line studies, acquired resistance to different cytotoxic agents is not associated with cross-resistance to HER1/EGFR kinase inhibitors.39,40
It is important to establish the differential molecular characterization of responding and nonresponding tumors to select patients with a higher probability of response. The lack of correlation between response and survival and HER1/EGFR expression observed in this study and in other studies with HER1/EGFR inhibitors35,41 suggests that successful patient selection could be highly complex. Potential explanations for this lack of correlation exist. Assessment of total receptor is not an accurate indicator of the level of activation of the HER1/EGFR pathway. Measurements of phospho-HER1/EGFR as well as coexpression of other components of the pathway or autocrine and paracrine loop, such as transforming growth factor alpha, might result in the development of more predictive algorithms. It is also likely that a certain level of intratumoral activation of the HER1/EGFR pathway may be a prerequisite for HER1/EGFR inhibitors to induce a tumor response. Alternative pathways that restore interrupted growth signaling may be turned on as a cellular response to HER1/EGFR blockade, so each individual tumor would have to be assessed for the capability to switch to these alternative pathways. Continued laboratory studies are needed to elucidate the mechanisms of action of erlotinib in more clinically relevant models than the high HER1/EGFR-expressing cell lines traditionally used. Genomic profiling and mechanistic studies in panels of human NSCLC tumors heterotransplanted in nude mice42 may provide clinically relevant information regarding the determinants of sensitivity and mechanisms of resistance to erlotinib.
In conclusion, this study indicates that erlotinib is an active and well-tolerated agent for the treatment of relapsing NSCLC and supports the continued clinical development of this promising agent. Whether the response rate and symptom improvement observed provide definitive clinical benefit to this patient population has been addressed in a randomized study against best supportive care conducted by the National Cancer Institute of Canada (BR.21). Results of this important trial were announced recently. Erlotinib significantly prolonged overall survival and improved symptoms in this patient population. These results are particularly interesting because two large randomized studies of erlotinib in combination with chemotherapy used as first-line treatment in patients with NSCLC showed no advantage with the addition of erlotinib. However, it is likely that the first-line studies were flawed because the combination schedule used was suboptimal. Recently, two independent studies have reported that most responses to the HER1/EGFR tyrosine-kinase inhibitor gefitinib (Iressa; AstraZeneca, Wilmington, DE) occur in tumors with mutations or deletions at the tyrosine-kinase site of the HER1/EGFR.43-44 Whether this is also true for erlotinib is being investigated. Frontline combination strategies using an optimized schedule and in populations selected based on molecular determinants of tumor response are now possible and clearly warranted.
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Authors’ Disclosures of Potential Conflicts of Interest
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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Gary M. Clark, OSI Pharmaceuticals, Inc; Roman Perez-Soler, Genentech, OSI Pharmaceuticals, Inc. Acted as a consultant within the last 3 years: Gary M. Clark, OSI Pharmaceuticals, Inc; Lisa A. Hammond, Genentech, and OSI Pharmaceuticals, Inc; Eric K. Rowinsky, OSI Pharmaceuticals, Inc; Roman Perez-Soler, Genentech, OSI Pharmaceuticals, Inc. Served as an officer or member of the Board of a company: Pedro Santabarbara, OSI Pharmaceuticals, Inc. Received more than $2,000 a year from a company for either of the last 2 years: Gary M. Clark, OSI Pharmaceuticals, Inc; Lisa A. Hammond, Genentech, OSI Pharmaceuticals, Inc, and Roche; Eric K. Rowinsky, OSI Pharmaceuticals, Inc.
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NOTES
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Supported by OSI Pharmaceuticals, Inc, Melville, NY.
Data was previously presented at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12–15, 2001; and at the 10th World Congress on Lung Cancer, Vancouver, Canada, 2003.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Submitted November 10, 2003;
accepted April 28, 2004.
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TOP
ABSTRACT
INTRODUCTION
