Erlotinib Maintenance for Patients with Advanced NSCLC
Abstract & Commentary
William Ershler, MD
Synopsis: In a multinational trial of erlotinib (Tarceva®) for patients with advanced NSCLC following conventional chemotherapy, improved progression-free and overall survival were demonstrated. The improvement was approximately one week for PFS and one month for OS. However, for the subset with demonstrable activating mutations in the EGFR gene, the benefit of erlotinib treatment was more substantial.
Source: Cappuzzo F, et al. Elotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomized, placebo-controlled phase 3 trial. Lancet Oncol. 2010;11:521-529.
First-line chemotherapy for advanced non-small cell lung cancer (NSCLC) is usually limited to four to six cycles, and results in responses or stable disease in about 80% of cases. Nonetheless, additional therapy (beyond four to six cycles) is associated with higher levels of toxicity without improving results, and overall survival remains approximately 11-12 months.1,2 When disease recurs, it is often very aggressive and associated with a decline in performance status, such that nearly half of those affected are not considered suitable for second-line chemotherapy.3,4 Accordingly, maintenance therapy, administered immediately after first-line treatment for those who responded (including those with stable disease) has been the focus of recent investigative interest.5
The oral epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib has proven efficacy and tolerability in second-line NSCLC.6,7 In a multinational phase 3, placebo-controlled trial conducted at 110 sites in 26 countries, and sponsored by Hoffmann-LaRoche, the use of erlotinib as maintenance therapy in patients with non-progressive disease following first-line platinum doublet chemotherapy was tested. Between December 2005 and May 2008, 1,949 patients were included in the run-in phase. For this, participating physicians chose one of seven platinum-based combinations for four cycles of initial chemotherapy. Upon completion of this initial therapy phase, 889 patients who did not have progressive disease were entered into the main study and were randomly allocated (1:1) to receive erlotinib (150 mg/day; n = 438) or placebo (n = 451) until progression or unacceptable toxicity. Patients were stratified by EGFR immunohistochemistry status, stage, Eastern Cooperative Oncology Group performance status, chemotherapy regimen, smoking history, and region. Co-primary endpoints were progression-free survival (PFS) in all analyzable patients irrespective of EGFR status and PFS in patients whose tumors had EGFR protein over expression, as determined by immunohistochemistry.
Of these patients, 884 patients were analyzable for PFS; 437 in the erlotinib group and 447 in the placebo group. After a median follow-up of 11.4 months for the erlotinib group and 11.5 months for the placebo group, median PFS was significantly longer with erlotinib than with placebo: 12·3 weeks for patients in the erlotinib group vs. 11·1 weeks for those in the placebo group (HR 0.71, 95% CI 0.62–0.82; p < 0·0001). PFS also was significantly longer in patients with EGFR-positive immunohistochemistry who were treated with erlotinib (n = 307), compared with EGFR-positive patients given placebo (n = 311; median PFS 12·3 weeks in the erlotinib group vs. 11·1 weeks in the placebo group; HR 0.69, 0.58–0.82; p < 0·0001). As expected among the small subset (n = 40), in which tumor DNA had demonstrable EGFR mutations, erlotinib maintenance provided the greatest benefit (HR 0.10, (0.04-0.25).
The most common grade 3 or higher adverse events were rash (37 [9%] of 443 patients in the erlotinib group vs. none of 445 in the placebo group) and diarrhea (seven [2%] of 443 patients vs. none of 445). Serious adverse events were reported in 47 patients (11%) on erlotinib compared with 34 patients (8%) on placebo. The most common serious adverse event was pneumonia (seven cases [2%] with erlotinib and four [< 1%] with placebo).
Commentary
The question of maintenance therapy for patients achieving benefit from initial platinum-based chemotherapy for advanced NSCLC has been raised before. Fidias and colleagues recently reported their experience with docetaxel given either immediately after initial platinum-based therapy compared with delayed (i.e., at the time of clinically apparent progressive disease). They found that overall survival was not different between the two groups, but 37% in the delayed group never received the planned therapy.3 In a similar trial in which pemetrexed was compared with placebo, approximately one-third of those randomized to placebo received only the induction therapy, whereas over half of the patients who received pemetrexed were treated with a third line of chemotherapy upon clinically recognized progression.8
In the current report, erlotinib was shown to be both well tolerated and successful in prolonging PFS and overall survival (OS), albeit by only small margin (PS, 12.3 weeks vs. 11.1 weeks for those receiving placebo; OS 12 months vs. 11 months for those receiving placebo). These improvements were apparent in the overall population, irrespective of EGFR status, and also irrespective of sex, ethnic origin, histology, or smoking status.
Should all NSCLC patients who have responded or achieve stable disease after initial chemotherapy receive erlotinib? On the positive side, it appears the drug is well tolerated and briefly prolongs PFS and OS. However, enthusiasm for such an approach must be balanced by fiscal reality; this is an expensive drug and the benefits, although statistically significant, are small. In the United States, three months of erlotinib retails at just short of $15,000. With the number of close to 200,000 new lung cancer patients each year, only a substantial fraction would be eligible. Conservatively, assuming this as a standard approach, it would cost over one billion dollars annually.
Erlotinib is an effective drug, with its greatest benefit for those patients who harbor discernible EGFR mutations. Its use in such patients is clearly justified. Its benefit for patients without EGFR mutation is present, but marginal, and there remains a need for developing more effective maintenance treatment for NSCLC.
References
1. Reck M, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009;27:1227-1234.
2. Williamson SK, et al. Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003. J Clin Oncol. 2005;23:9097-9104.
3. Fidias PM, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27(4):591-8.
4. Socinski MA, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol. 2002;20:1335-1343.
5. Stinchcombe TE, Socinski MA. Treatment paradigms for advanced stage non-small cell lung cancer in the era of multiple lines of therapy. J Thorac Oncol. 2009;4:243-250.
6. Bezjak A, et al. Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 2006;24:3831-3837.
7. Shepherd FA, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123-132.
8. Ciuleanu T, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374:1432-1440.
In a multinational trial of erlotinib (Tarceva®) for patients with advanced NSCLC following conventional chemotherapy, improved progression-free and overall survival were demonstrated. The improvement was approximately one week for PFS and one month for OS. However, for the subset with demonstrable activating mutations in the EGFR gene, the benefit of erlotinib treatment was more substantial.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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