Chandra Belani, MD: Lung cancer chemotherapy overview

Interviewed by Steven Greer, MD

Dr. Chandra Belani, Deputy Director, Penn State Cancer Institute, discusses the latest standard of care for NSCLC non-small cell lung cancer.

Chandra Belani, MD: Maintenace therapy for NSCLC

By Chandra belani, MD

Miriam Beckner Professor of Medicine, Penn State College of Medicine, Deputy Director, Penn State Hershey Cancer Institute

Until now, we have only seen futility of prolonged administration of combination chemotherapy regimen(s) beyond 3 to 4 cycles in patients with advanced NSCLC. This was hypothesized to be due to the rarity of response after the first 4 cycles of chemotherapy and the cumulative toxicities associated with prolonged administration of combination regimens. Extending therapy with a well-tolerated and effective agent(s) in this palliative setting may in fact be advantageous for a patient with advanced NSCLC.

The favorable tolerability profile of pemetrexed and the ability to administer for extended number of cycles lend itself for evaluation as maintenance therapy. Our phase III study^{1, 2} compared pemetrexed (500 mg/m2 every 3 weeks) to placebo in patients who achieved stable disease or objective response with 4 cycles of platinum-based therapy in advanced NSCLC patients. There was a significant improvement in median PFS (4 m vs. 2.0 m) and median overall survival (13.2 m vs. 10.6 m, P=0.012). The magnitude of benefit was significantly higher in the non-squamous histology group where the improvement in survival was > 5 months (15.5 m vs. 10.3 m, P = 0.002) with maintenance pemetrexed. The safety results for patients treated with pemetrexed were consistent with its known safety profile described in product labeling. Thus, maintenance pemetrexed can now be considered a new therapeutic option and a step in the right direction, as it improves the outcome for patients with advanced non-squamous NSCLC. The nod, both from the European Medicines Agency and the Food and Drug Administration, for use in the maintenance setting in the non-squamous subset validates the concept of this new treatment paradigm.

The criticism regarding use and availability of pemetrexed for the placebo group at the time of progression is valid to an extent, but the survival data are so provocative that they trump everything else. Only 19% of the patients in the placebo group received pemetrexed at the time of progression as it was not available for use, but 67% of the patients did receive approved second-line therapies. Decline in performance status and overall deterioration is the main reason for at least a third to half of the patients who do not make it to second-line ‘effective therapy’ if they get a treatment break. Most of these patients progress after a short interval and despite close follow-up even in the study setting may fail to make it to the next-line of treatment. There is no realistic way of predicting whether a patient will benefit from such a break or have rapid progression and a downhill course making an argument in favor of maintenance therapy. While it is of utmost importance to individualize or personalize maintenance therapy, and ‘histology’ does matter as demonstrated by the prespecified analysis of the pemetrexed maintenance trial, there may be a role of molecular determinants of pemetrexed sensitivity in NSCLC.

The toxicities of pemetrexed are mild at best and there were no cumulative toxicities lending further credence to its use and taking the treatment of advanced non-squamous cell carcinoma to the next level.

Furthermore, the concept of maintenance therapy has received validation by the recently reported survival data from the SATURN study, where erlotinib, an EGFR tyrosine kinase inhibitor, was evaluated as maintenance therapy.³ Dr.Capuzzo presented the results both at ASCO 2009 and WCLC 2009.^3,4 Following 4 cycles of platinum-based combination therapy, patients with CR, PR or SD were randomized to treatment with erlotinib or placebo. Out of a total of 1949 patients enrolled, 889 with disease control were able to be randomized, a relatively small number. There was an improvement in median PFS was improved with erlotinib with a hazard ratio of 0.71. The hazard ratio was most favorable for patients with EGFR mutated tumors at 0.10. The survival results also favored erlotinib (HR 0.81) with a 1 month benefit in median survival in the erlotinib treated group (12 months vs. 11 months). It seems that the magnitude of benefit is tremendous in the patients with tumors demonstrating mutations of the EGFR tyrosine kinase domain. Though the presenter made the comment that the patients with wild-type tumors also show a benefit, but again this may not be clinically meaningful. Erlotinib is an appealing option in the presence of EGFR mutation, not only in the maintenance setting but also in the first-line, second-line or any-line of therapy. The results of the study by Miller and colleagues⁵ also supported the benefit of erlotinib on PFS in the maintenance setting in the ‘bevacizumab eligible’ patients with advanced NSCLC. Following 4 cycles of treatment with chemotherapy and bevacizumab, those with a CR/PR or SD were randomized to continue bevacizumab alone or in combination with erlotinib. The hazard ratio for PFS was 0.72 but the overall survival results are not available to make valid comparisons to the other two studies. The role of maintenance bevacizumab cannot be gauged from the trial because of a lack of a ‘placebo’ arm in the trial and patients on both arms received bevacizumab. The toxicities with the combination are substantial (table 2).

Thus maintenance therapy of advanced NSCLC is a reasonable ‘evidence-based approach’ and an addition to the treatment armamentarium for patients with advanced disease. Substantial improvement in survival outcome in the non-squamous histology with pemetrexed leading to its approval by the regulatory agencies strengthens it case for use in this setting. In addition ‘maintenance therapy concept’ changes the way we will design future clinical trials for patients with advanced NSCLC.

References:

1. Belani CP, Brodowicz T, Ciuleanu T, et al. Maintenance pemetrexed (Pem) plus best supportive care (BSC) versus placebo (Plac) plus BSC: A randomized phase III study in advanced non-small cell lung cancer (NSCLC). J Clin Oncol; 27:18s, 2009 (suppl; abstr CRA8000).

2. Ciuleanu T, Brodowicz T, Zielinski, et al. Maintenance Pemetrexed Plus Best Supportive Care (BSC) Versus Placebo Plus BSC: A Phase III Study in Advanced NSCLC. 10.1016/S0140-6736(09)61497-5, The Lancet, Early Online Publication, 20 September 2009.

3. Cappuzzo F., Ciuleanu T, Stelmakh, et al. SATURN: A double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. WCLC JTO 2009 (suppl; abstr 8001).

4. Cappuzzo F., Ciuleanu T, Stelmakh, et al. SATURN: A double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol; 27:18s, 2009 (suppl; abstr 8001).

5. Miller VA, O’Connor P, Soh C, Kabbinavar F for the ATLAS Investigators. A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol; 27:18s, 2009 (suppl; abstr LBA8002)

6. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after frontline therapy with gemcitabine plus carboplatin in advanced non-small cell lung cancer. J Clin Oncol; 27(4):591-8, 2009.