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Novel Agents in the Treatment of Lung Cancer |
Author's Affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
Requests for reprints: Kwok-Kin Wong, Department of Medical Oncology, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, D810, Boston, MA 02115. Phone: 617-632-6084; E-mail: Kwong1{at}partners.org.
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Abstract |
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 Top Abstract Lung Cancer and the...EGFR Kinase Domain Mutations...Preclinical Studies with HKI-272Lung Cancer Clinical Trials...Open DiscussionReferences |
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10% of lung adenocarcinomas sequenced in the United States and in 30% sequenced in Asia. These mutations are associated with sensitivity to the EGFR inhibitors gefitinib and erlotinib. Many patients who initially respond to erlotinib or gefitinib subsequently relapse. Studies have identified EGFR T790M mutations in tumors from patients who initially responded and then relapsed. The T790M mutation, when combined in vitro with treatment-sensitizing EGFR mutations, permits the continued growth of tumor cells in the presence of erlotinib and gefitinib. HKI-272 is an irreversible EGFR/HER/ErbB inhibitor that has been shown to inhibit the growth of T790M mutant cells in vitro in human lung cancer cell lines and in murine cells transfected with sensitizing EGFR mutations. A phase I HKI-272 monotherapy trial in patients with solid tumors is close to completion. Preliminary analyses of the trial, presented at the 2006 annual meeting of American Society of Clinical Oncology, showed that HKI-272 can achieve stable disease control for over 6 months in some patients with non–small cell lung cancer that has progressed after treatment with gefitinib or erlotinib. A phase II trial of HKI-272 in non–small cell lung cancer patients has been initiated. HKI-272 might offer benefits to non–small cell lung cancer patients who have relapsed after an initial response to erlotinib.
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Lung Cancer and the Epidermal Growth Factor Receptor Signaling Pathway |
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TopAbstractLung Cancer and the...EGFR Kinase Domain Mutations...Preclinical Studies with HKI-272Lung Cancer Clinical Trials...Open DiscussionReferences |
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, are expressed in over 80% of NSCLC (1, 2). It is a member of the ErbB family of receptors that includes EGFR (ErbB1), HER2/neu (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Upon ligand binding, EGFR homodimerizes or forms heterodimers with other members of the ErbB family, resulting in receptor phosphorylation and activation of downstream signaling events. Activated EGFR associates with multiple signaling mediators, such as Shc, Grb2, Src, JAKs, PLD, PLC
, and PI3K, and subsequently to the activation of signaling transducers, such as ERK1/2, FAK, JNK, STATs, and Akt, resulting in increases in cellular proliferation, motility, adhesion, and invasion, as well as resistance to apoptosis and chemotherapy (3–5). |
EGFR Kinase Domain Mutations and Lung Adenocarcinomas |
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TopAbstractLung Cancer and the...EGFR Kinase Domain Mutations...Preclinical Studies with HKI-272Lung Cancer Clinical Trials...Open DiscussionReferences |
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10% of lung adenocarcinoma specimens sequenced in the United States and 30% sequenced in Asia. The mutations are associated with sensitivity to both gefitinib and erlotinib, explaining in part the rare dramatic clinical responses to treatment with these agents (11–13). Subsequent studies by multiple groups have now identified EGFR kinase domain mutations from many additional lung cancer patients (14, 15). The gefitinib and erlotinib sensitizing mutations are clustered in three groups: exon 19 deletions and point mutations at G719S and L858R. Thus far, it seems that these kinase domain mutations are more common in adenocarcinomas than in other histologic subtypes of lung cancers, such as squamous cell carcinoma (10, 15). Recent emerging data also suggest that EGFR expression assessed by immunohistochemistry and the EGFR gene copy number might play equally important roles in identifying patients more likely to respond and have longer survival when treated with gefitinib or erlotinib (10, 16). Nearly all patients who initially respond to erlotinib and gefitinib subsequently relapse. Three studies identified EGFR T790M mutations in tumors from patients who relapsed (17–19). In tumor cells that have the sensitizing EGFR kinase domain mutation, these mutants permit continued tumor growth in the presence of erlotinib and gefitinib. Two irreversible inhibitors of EGFR, CL-387,785 and HKI-272, have been shown to inhibit the growth of the T790M resistance mutants in vitro and offer a promising approach to treatment of tumors with acquired resistance (17, 18). Of these two agents, only HKI-272 (Wyeth Pharmaceuticals) is presently in advanced clinical development. It should also be noted that other irreversible EGFR inhibitors, such as BIBW 2992 (Boehringer Ingelheim) and PF299804 (Pfizer), are also being tested clinically in this patient population, although no data have been published regarding their efficacy against the T790M mutation in vitro.
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Preclinical Studies with HKI-272 |
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TopAbstractLung Cancer and the...EGFR Kinase Domain Mutations...Preclinical Studies with HKI-272Lung Cancer Clinical Trials...Open DiscussionReferences |
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Lung Cancer Clinical Trials with HKI-272 |
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TopAbstractLung Cancer and the...EGFR Kinase Domain Mutations...Preclinical Studies with HKI-272Lung Cancer Clinical Trials...Open DiscussionReferences |
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1) for either HER2 or EGFR on immunostaining done by an independent testing company. The maximum tolerated dose was determined to be 320 mg from this phase I study, with diarrhea as the primary adverse effect and dose-limiting toxicity. Although not the primary objective of the trial, encouraging clinical activity from this study was reported at the 2006 annual meeting of American Society of Clinical Oncology (24). Among the 23 evaluable breast cancer patients enrolled into the trial, there were seven confirmed partial responses and one patient with stable disease for >24 weeks. The duration of responses was 7 to 24 weeks with four patients still on study as of the American Society of Clinical Oncology presentation. Among the 12 evaluable NSCLC patients, there were no confirmed responses but five of these patients (who had progressed on erlotinib or gefitinib) achieved stable disease for >24 weeks.
A phase II HKI-272 trial in NSCLC patients has recently been initiated. This is a multiinstitution trial (funded by Wyeth Pharmaceuticals) with a planned accrual of 138 patients divided equally among three study arms (Fig. 1 ). For entry into two (A and B) of the three arms, eligible patients must have disease progression after at least 12 weeks of erlotinib or gefitinib therapy. Those with EGFR kinase mutations are entered on arm A, and those whose tumors are wild type for EGFR are entered on arm B. Patients with no prior erlotinib or gefitinib therapy are enrolled on arm C. Tumor sequencing of EGFR exons 18 to 24 is included in the entry criteria for all patients and will be done by Genzyme Genetics, which is certified under the Clinical Laboratory Improvement Amendments program. All patients enrolled into the trial will receive 240 mg HKI-272/day, orally, continuously until progression of disease or development of unacceptable treatment-related toxicity. An optional tumor biopsy for patients who exhibit a response while on the trial but subsequently progress is part of the protocol. These tumors with acquired resistance to HKI-272 will then be sequenced for secondary EGFR kinase domain mutations. The EGFR mutation status data collected before and after treatment with HKI-272 will aid in defining the mechanisms of biological response to this inhibitor based on the type of EGFR kinase domain mutations that are identified in responding patients, as well as in patients with primary and acquired HKI-272 resistance.
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Open Discussion |
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TopAbstractLung Cancer and the...EGFR Kinase Domain Mutations...Preclinical Studies with HKI-272Lung Cancer Clinical Trials...Open DiscussionReferences |
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Dr. Wong: About 3% to 5% of patients have HER2 amplification, and HER2 mutation has also been found in non–small cell lung cancer at about 1% to 2%. I think those patients would actually derive more benefit than the T790M patients, at least with the data that we have. Looking at the preclinical data, we would predict the patients who would derive benefit from HKI-272 would be the ones with L858R plus T790M. Unfortunately, those patients never make it that far because they don't do as well as on erlotinib as those with the deletion mutations.
Dr. Jeffrey Engelman: These patients are not getting rashes, so do you think this agent is inhibiting wild-type EGFR in patients? It looks as though this basically a HER2 inhibitor in patients.
Dr. Roman Perez-Soler: There were about six responses in 30 patients with breast cancer and none in 12 patients with lung cancer.
Dr. Lynch: There are several pan ErbB inhibitors in various stages of development. The good thing about this study is the concept of using selection of patients based on mutation status to gain some insight. Thinking more about this class of compounds, do you think it is likely that what we will be screening people for mutations up-front and selecting patients for one versus another? Do you think that this kind of work will predict how patients will do clinically?
Dr. Wong: The different structures of the EGFR inhibitor compounds affect they interact with the protein. Depending on the mutation, some might go into the pocket easier and have a different potency. I believe that 5 years from now we are going to have a half dozen of these compounds in clinical development and patients will be stratified based on what particular mutations they have.
Dr. Bruce Johnson: The mutation sequencing on the HKI-272 trials is done at any time point during the clinical course. Very few have their biopsy done right before they get the drug. So, the numbers for which you will know the T790M status at the time they start treatment with HKI-272 are going to be small.
Dr. Lecia Sequist: That's another change we need to make in our paradigm in caring for patients if we are really going to use these molecular markers, because we have to rebiopsy after people progress.
Dr. Lynch: Dr. Socinski, you have done a large number of clinical trials in lung cancer; is it feasible for a second-line study to mandate a repeat biopsy at progression?
Dr. Mark Socinski: I think it is feasible and probably important, because what you are dealing with clinically at that point might not be reflected by a biopsy that was done 15 months earlier. We did some of the phase I lapatinib studies in which there were serial biopsies that needed to be done and they got done.
Received 2/13/07; accepted 3/12/07.
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TopAbstractLung Cancer and the...EGFR Kinase Domain Mutations...Preclinical Studies with HKI-272Lung Cancer Clinical Trials...Open DiscussionReferences |
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  D. B. Costa, K.-S. H. Nguyen, B. C. Cho, L. V. Sequist, D. M. Jackman, G. J. Riely, B. Y. Yeap, B. Halmos, J. H. Kim, P. A. Janne, et al. Effects of Erlotinib in EGFR Mutated Non-Small Cell Lung Cancers with Resistance to Gefitinib Clin. Cancer Res., November 1, 2008; 14(21): 7060 - 7067. [Abstract] [Full Text] [PDF]
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