Clinical Cancer Research 13, 4589s, August 1, 2007. doi: 10.1158/1078-0432.CCR-07-0541
© 2007 American Association for Cancer Research
Novel Agents in the Treatment of Lung Cancer |
Erlotinib: Recent Clinical Results and Ongoing Studies in Non–Small Cell Lung Cancer
Roman Perez-Soler
Author's Affiliation: Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
Requests for reprints: Roman Perez-Soler, Department of Oncology, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467-2490. Phone: 212-920-4001; Fax: 718-798-7474; E-mail: rperezso{at}montefiore.org.
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Abstract
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The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib has shown to provide clinical benefit to patients with non–small cell lung cancer (NSCLC) after failure of front-line chemotherapy in a double-blind placebo-controlled clinical trial. More importantly, because of its unique mechanism of action, erlotinib seems to provide higher clinical benefit to specific subgroups of patients. The continued development of erlotinib in NSCLC is focused on the following areas: (a) validating clinical and molecular markers of clinical benefit in front-line therapy, (b) developing therapies for acquired and naturally resistant tumors, (c) revisiting combinations with chemotherapy, (d) developing combinations with antiangiogenesis agents, and (e) understanding the biological significance of the skin toxicity and developing rational approaches for its treatment. Clinical studies addressing these five areas are ongoing and are briefly described in this review.
The BR.21 study definitively established that erlotinib is effective in NSCLC patients as second- and third-line therapy in a nonselected patient population (1). Retrospective subset analyses based on clinical characteristics indicate that a majority of subgroups derive clinical benefit, including smokers, Caucasians, males, squamous carcinomas, and performance status (PS) 2 and 3 patients, patients with a history of smoking being the group deriving less benefit and never smokers and east Asians the groups deriving more benefit. Analyses of subsets based on molecular characteristics led to the same conclusion, as hazard ratio (HR) values <1 were observed in patients with wild-type epidermal growth factor receptor (EGFR) as well as in those EGFR negative by immunohistochemistry (IHC) and by fluorescence in situ hybridization (FISH), with patients with high gene copy number being the group deriving more benefit. (2). The only subset of patients with a HR >1 were those with K-ras–mutated tumors (HR, 1.51; ref. 3). The results of these retrospective analyses justify conducting clinical trials of erlotinib both as front-line and second-line therapy in selected populations of patients, but cannot be used to rationally determine clinical practice guidelines for patients with NSCLC receiving second- and third-line therapy. Erlotinib is currently a valid therapeutic option for all patients as second- or third-line therapy. Prioritization of the three agents approved for these indications remains an empirical decision because there are no subset analysis data for the other approved agents, pemetrexed and docetaxel, in the context of their pivotal studies. To aid in decision making in the clinical setting, ongoing studies will endeavor to validate and refine the clinical and molecular variables that predict clinical benefit with erlotinib, to investigate its efficacy in combination with other approved and investigational agents, and to better manage associated toxicity.
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Validation of Determinants of Clinical Benefit in Front-Line Therapy Studies
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The information from subset analyses in the BR.21 study provides useful guidance in the design of front-line therapy trials with erlotinib alone or in combination that could benefit many patients by providing a superior or less toxic alternative to cytotoxic chemotherapy. The need for a rational basis for therapy selection seems stronger after the results of a randomized phase II study of erlotinib versus carboplatin and paclitaxel as front-line therapy in patients with PS 2 showed an advantage for combination chemotherapy (4). Using information derived from the BR.21 study, by order of higher to lower hazard ratios, determinants that would seem worth exploring alone or in combination as negative selectors in front-line studies include K-ras mutations, EGFR negativity by IHC, positive smoking history, FISH negativity, and EGFR wild type. Similarly, determinants that could be used as positive selectors include never smoker and FISH positivity. Nonsmoking status remains one of the strongest predictors of clinical benefit with erlotinib and has been observed in all trials with erlotinib and gefitinib, used either alone or in combination with chemotherapy. Because of the unexpected discrepancy with regard to the value of EGFR mutations in predicting clinical benefit between the BR.21 study and many phase II studies, the presence of EGFR mutations remains a potential positive selector pending definitive validation studies. Beyond the BR.21 study, new information on other possible molecular markers has been recently generated, particularly through the use of serum proteomics, an approach which seems very promising and possibly more amenable to widespread clinical use (5). Confirmation of the serum proteomics findings in serum samples from the BR.21 study would be an important step toward validating this new technology.
Many clinical trial designs using one or more of these selectors as entry criteria are possible, and they are all valid because it is impossible to predict which combinations of selectors would be optimal in accurately identifying the population that would derive meaningful clinical benefit from front-line erlotinib. A very restrictive approach might result in a positive study, but at the price of excluding many patients that still could derive clinically relevant benefit. On the other hand, a less restrictive approach increases the risk of a negative study because patients that do not derive any benefit are included. Several studies that use positive or negative selection in front-line or adjuvant therapy using some of these selectors are being implemented: CALGB 30406 (nonsmokers), Spanish Lung Cancer Study Group (EGFR mutations; ref. 6), and the RADIANT adjuvant study (EGFR-positive status by IHC and FISH), among others.
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Development of Therapies for Tumors with Acquired or Natural Resistance to Erlotinib
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Acquired resistance to erlotinib in EGFR-mutated tumors has been found to be associated with the emergence of a second EGFR mutation in 30% to 50% of cases (7). Agents potentially effective against the double-mutated EGFR are being actively investigated, and those studies are summarized in other papers included in these conference proceedings. Natural resistance has been associated in many experimental systems with the inability to inhibit the downstream pathways. In tumors with K-ras mutations, activation of the mitogen-activated protein kinase pathway is under the control of the mutated K-ras protein and not affected by upstream inhibition of EGFR. To address naturally occurring resistance, combinations of anti-EGFR agents with inhibitors of downstream elements of the pathway are being investigated.
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Revisiting Combinations with Chemotherapy
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The negative results of the chemotherapy plus erlotinib front-line trials TALENT and TRIBUTE (8, 9) have generated the general belief that erlotinib may never have a role in combination with chemotherapy in the treatment of NSCLC. However, the combination of gemcitabine and erlotinib was more effective than gemcitabine alone as front-line treatment of pancreatic carcinoma in the PAN3 study (10). In addition, the anti-EGFR antibody cetuximab has been approved for refractory colorectal and head and neck cancer in combination with irinotecan and radiation therapy, respectively. However, more recently, the anti-EGFR antibody panitumumab did not enhance the antitumor activity of carboplatin and paclitaxel as front-line therapy in NSCLC (11). There is no convincing explanation for all these discrepant results. One of the hypotheses proposed to explain many of these observations is that the continuous administration of an EGFR tyrosine kinase inhibitor (TKI) may induce a robust G1 cell cycle arrest in cells sensitive to EGFR inhibition that prevents the cytotoxic effect of chemotherapy on subsequent courses (12). Such a cell cycle blockade is not observed in cells resistant to EGFR inhibition such as cells with K-ras mutations, present in about 30% of lung adenocarcinomas and in more than 90% of pancreatic carcinomas. However, in some of the K-ras–mutated tumors, the cytotoxic effect of chemotherapy may trigger an EGFR-mediated survival response through the activation of the AKT pathway that may be abrogated by the EGFR TKI, thus providing a plausible explanation for the superiority of the combination in the PAN3 pancreatic carcinoma trial (13). Intermittent administration schedules that minimize antagonism by separating the pharmacodynamic effects of both types of agents are now being explored both in front-line therapy with carboplatin and paclitaxel combinations and in second-line therapy with docetaxel and pemetrexed. In these trials, erlotinib is administered on days 2 to 16 and 17, thus allowing for cell cycle recovery before chemotherapy is administered on day 21.
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Combinations with Antiangiogenesis Agents
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Combinations of anti-EGFR agents with antiangiogenesis agents have been proposed as a strategy for reinforced antiangiogenesis therapy because inhibition of EGFR affects the production of proangiogenic mediators by tumor cells. Two basic strategies are being studied. The first involves the use of two agents, like erlotinib and bevacizumab, and the second involves the use of a dual TKI like vandetanib (ZD6474) that inhibits both the EGFR and the vascular endothelial growth factor receptor (VEGFR). Both strategies have shown promising results. Two phase II studies of the combination of erlotinib and bevacizumab as second-line therapy for lung adenocarcinoma have shown response rates and 6-month survival rates in the range of 15% to 20% and 75%, respectively, that seem higher than those observed with erlotinib alone, second-line chemotherapy alone, or multitargeted TKIs like sorafenib and sunitinib. The combination of chemotherapy and bevacizumab also seemed superior to chemotherapy alone (14, 15). A large randomized phase III study to definitively show superiority with the combination is in progress (Beat Lung trial). Phase II randomized studies with vandetanib, alone or in combination with docetaxel, have also shown superiority compared with gefitinib alone or docetaxel alone (16, 17). As a result, vandetanib is also being tested in large randomized trials against erlotinib as single agent or in combination with docetaxel against docetaxel alone. It is reasonable to expect that some of these trials may be positive and justify the use of this dual blockade approach in second-line therapy. The only caveat is that the results of these studies may not be applicable to patients who have failed front-line chemotherapy that included bevacizumab.
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Treatment of the Skin Toxicity
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Skin toxicity secondary to therapy with EGFR inhibitors remains a significant clinical problem. With the corroboration in the BR.21 study that skin toxicity and survival are clearly correlated (18), the use of the skin toxicity as a surrogate marker of clinical benefit continues to be an important area of investigation. Dose reduction to ameliorate skin toxicity is, in principle, a less attractive strategy than using an effective treatment for the skin toxicity without dose reduction. Unfortunately, current treatments for skin toxicity, which involve combinations of topical or systemic steroids, antibiotics, antihistamines, and immunosuppressive agents, are purely empirical and often unsatisfactory. Rational therapies for this condition are urgently needed. We have hypothesized that a possible way to abrogate the effects of anti-EGFR agents at the receptor level would be by inhibiting the phosphatase. The baseline phosphorylation status of EGFR depends on phosphatase activity. If such activity was effectively inhibited, EGFR would remain fully and constantly phosphorylated, and competition between ATP and erlotinib for the ATP binding sites would be abolished. We have identified that vitamin K3, among other effects, has phosphatase-inhibiting action, and that its topical application in the skin of mice can abrogate the effect of oral erlotinib (19). A topical formulation of vitamin K3 at the appropriate strength is being developed, and clinical trials are expected to start within a few months. Whether effective prevention or treatment of the skin toxicity may affect the antitumor effect of erlotinib is unknown at this point.
The need of dose escalation in the absence of skin toxicity remains speculative because it is not known whether the lack of skin toxicity is due to low plasma drug levels or an intrinsic lack of susceptibility of the skin to the inhibitory effect of the drug. Dose escalation to achieve a certain level of skin toxicity in all patients is investigated in dose-to-rash studies. Dose escalation until skin toxicity is observed may be important in patients with an enhanced liver metabolism such as active smokers (20) or patients on certain common medications like diphenylhydantoines.
In conclusion, erlotinib has become part of the therapeutic armamentarium for NSCLC. Because of the extensive knowledge available on its biological and pharmacologic properties, it is reasonable to assume that the ongoing clinical studies will result in more refined and rational guidelines for its use in patients with NSCLC.
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Open Discussion
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Dr. Thomas Lynch: Do people think there are dose questions with erlotinib that need to be answered?
Dr. Perez-Soler: I think definitely in active smokers. If it is true that active smokers have an AUC that is three times lower than ex- or never smokers, I think you have enough rationale to justify a clinical experiment.
Dr. Mark Socinski: The BR.21 data suggest that anti-EGFR therapy is not helpful in the heavy smoker. So, is that a dose question?
Dr. Perez-Soler: Probably it is in active smokers. I think it is appropriate to ask again a phase I question in a specific subset of patients so that we avoid undertreating them.
Dr. Philip Bonomi: If you look at rash in current versus nonsmokers, is there a difference? You see the AUC differences, but do you see any clinical effect?
Dr. Perez-Soler: Yes, if you talk to Gary Clark at OSI Pharmaceuticals, he will tell you there is less rash in the smokers in the BR.21 trial. I cannot tell you how much. I think the data will be published soon.
Dr. Roy Herbst: There have been anecdotal reports of raising the dose in responders with the mutation who develop secondary resistance and progress, particularly those who don't have rash. Has anyone in the room tried that?
Dr. Bruce Johnson: We had a person with a deletion mutant who developed carcinomatous meningitis. We pushed the dose up to 1,000 to 1,250 mg per day of gefitinib. We saw a response in the central nervous system but did not see it systemically. When we did the molecular analysis, we found the resistance mutation was present systemically but not in the CNS. So pushing the dose has little or no effect if there is a T790 mutation.
Dr. Gregory Riely: We have increased the dose in a handful of patients. With erlotinib, it is tough to get much higher than 200 or 250 mg, and we have not seen dramatic responses, only continuation of stable disease.
Dr. Lynch: I would like to ask the group how they think erlotinib will be used in first-line and subsequent therapy 5 years from now.
Dr. Jeffrey Engelman: I don't think erlotinib will be used at all. I think there are going to be more potent TKIs that will inhibit T790M off the bat.
Dr. John Heymach: I agree that in the long run, we are going to want to be inhibiting T790M upfront instead of waiting for it to emerge. In terms of displacing erlotinib, that is not something that can happen in 5 years, if you just think of the time it takes for phase III studies to happen. I think we will be adding agents to erlotinib upfront to prevent emergence of resistance.
Dr. Charles Butts: I think we will have better selectors for who, when, and where to use erlotinib, probably as first-line therapy in a selected population.
Dr. Renato Martins: In terms of molecular predictors of benefit and this issue of mutation, I found that paper presented at ASCO [J Clin Oncol 2006;24(18S):7003] perplexing, because how can you shift progression-free survival to 13 months and have no impact on survival? That just does not make any sense.
Dr. Bruce Johnson: One has to be careful interpreting the molecular marker data that comes from those BAC studies; that is a very unusual subset of patients with lung cancer. It is highly selected for people who have not smoked very much. There appears to be increased copy number and receptor present in those tumors, and so extrapolating that to a broader experience is fraught with hazards.
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Footnotes
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Grant support: NIH CA 91784 and 113630.
Presented at the Fourth Cambridge Conference on Novel Agents in the Treatment of Lung Cancer, Cambridge, Massachusetts, September 29-30, 2006.
Received 3/ 5/07;
revised 5/ 9/07;
accepted 5/10/07.
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References
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Abstract
Validation of Determinants of...
