Novel Agents in the
Treatment of Lung Cancer
New Approaches to First-Line Therapies
Pemetrexed, Docetaxel, and Erlotinib in Maintenance Therapy
The treatment of metastatic NSCLC remains a daunting challenge. Survival times have improved modestly over the last 2 decades with the introduction of newer agents such as docetaxel, pemetrexed, and erlotinib. However, despite some progress, most patients will succumb to their disease in a matter of months, not years. Researchers have attempted to improve outcomes by a variety of strategies including dose intensification, alternating chemotherapy agents, early second-line therapy, and maintenance therapy. The inability to tolerate prolonged or intensified therapy limited these efforts in the past, but improved supportive care and agents with fewer side effects have allowed researchers to revisit these strategies.
Renewed interest in the use of consolidation therapy (initiating a different treatment prior to disease progression following a fixed number of cycles4 in the first-line setting) was provided by a study from Fidias et al. published in 2009.73 In that study, patients with advanced NSCLC were initially treated with carboplatin and gemcitabine for 4 cycles. If patients experienced progressive disease (PD), they were not randomized. Patients with stable disease (SD), partial response (PR), or complete response (CR) were randomized to receive docetaxel at 75 mg/m2 IV once every 3 weeks or were observed and treated with docetaxel at the time of PD. Approximately 300 patients were randomized to either arm. Patients treated on the immediate docetaxel arm experienced a prolonged progression-free survival (PFS) of 5.7 months compared with 2.7 months for those on the delayed arm (P=0.0001) (Figure 3). The improved PFS was not associated with improved quality of life (QoL) scores. In addition, median survival was prolonged (12.3 months vs 9.7 months; P=0.085) for those receiving immediate docetaxel therapy (Figure 4). While highly suggestive of improved outcomes, several caveats should be mentioned regarding this trial. First, patients on the delayed treatment arm were mandated for CT imaging only every 3 months. While patients were allowed to be reimaged more frequently, it is likely that some patients would have experienced asymptomatic progression prior to confirmation on CT imaging. What effect this additional delay in therapy had is not known. Secondly, PFS as an endpoint is valid only if imaging is performed at the same intervals on each arm, which may not have been the case in this study. Thirdly, nearly 40% of patients on the delayed arm never received docetaxel at the time of disease progression for a variety of reasons. Of those who did receive docetaxel on the delayed arm, their survival was nearly identical to patients receiving immediate docetaxel.
Nevertheless, despite these "flaws," this trial strongly supports the efficacy of docetaxel as second-line therapy in advanced NSCLC, and the inability to receive this agent was clearly detrimental for many patients. Should physicians therefore ensure that patients receive this agent without delay prior to disease progression following first-line therapy? While the study by Fidias was suggestive of improved maintenance of response following first-line therapy leading to improved PFS, the study failed to meet its primary aim of improved overall survivial (OS) (P=0.085). In addition, many other trials have failed to demonstrate improved efficacy with maintenance therapy. Additional trials were warranted prior to a change in the standard of care, which includes a treatment break after first-line therapy and initiation of second-line therapy only at the time of progression. Confirmatory results of improved efficacy with maintenance therapy seemed to have been obtained in 2009 from studies reported by Ciuleanu et al. and Cappuzzo et al. utilizing maintenance pemetrexed and erlotinib, respectively.74,8
Ciuleanu et al. treated chemonaive patients with advanced NSCLC using 4 cycles of chemotherapy.74 Patients with SD, PR, or CR to first-line therapy were entered onto the study and randomized in a 2:1 fashion to pemetrexed 500 mg/m2 IV once every 3 weeks (n=441) or to placebo (n=222). Baseline characteristics at the time of randomization were well balanced (although baseline characteristics prior to any therapy were not reported). Patients receiving pemetrexed experienced improved PFS (4 months vs 2 months, P=0.00001) compared with those on the placebo arm. Improved PFS did not translate into improved QoL. The improved PFS favoring the pemetrexed arm was observed only for patients with nonsquamous histology. In addition, median survival was improved for those on the pemetrexed arm (13.4 months vs 10.6 months, P=0.012). Median survival was improved an additional 5 months for those with nonsquamous histology, while patients with squamous histology had similar outcomes on either arm. Pemetrexed was generally well tolerated, with few grade 3 or 4 toxicities. It is worth noting, however, that pemetrexed does result in grade 1 and 2 rash, fatigue, nausea, and diarrhea, symptoms that are not trivial for patients. More than half of the patients on each arm received subsequent therapy off-study, although only 19% of patients on the placebo arm received pemetrexed. The outcomes for these patients have not been reported. Equal number of patients on each arm received gefitinib, erlotinib, or docetaxel, although this would be considered third-line and beyond therapy for patients on the pemetrexed arm, while it would only have been second-line and beyond therapy on the placebo arm. These data clearly underscore the efficacy of pemetrexed use in patients with nonsquamous NSCLC. The U.S. Food and Drug Administration (FDA) recently expanded the use of pemetrexed to include the maintenance setting.
Cappuzzo et al. reported the results of a similar trial as that of Ciuleanu et al., but utilizing maintenance erlotinib instead of maintenance pemetrexed.8 In this study, patients with advanced NSCLC were treated with 4 cycles of chemotherapy containing a platinum agent and either a taxane or gemcitabine. Patients with SD, PR, or CR were then randomized in a 1:1 fashion to either erlotinib 150 mg orally daily (n=438) or placebo (n=451). The primary end point of the trial was PFS. Patients receiving erlotinib experienced improved PFS compared with those on placebo (HR 0.71, P=0.0001), although there was no difference in median PFS (2.8 months vs 2.5 months). Patients with EGFR mutations had a substantial improvement in PFS (HR 0.1) favoring erlotinib, while those with EGFR wild-type tumors had a more modest improvement (HR 0.78). Improved PFS was noted in patients with either adenocarcinoma or squamous cell carcinoma. Updated results reported by Genentech in a press release indicate that median OS was improved by 1 month, favoring patients on the erlotinib arm. Only 16% of patients on the placebo arm received treatment with an EGFR TKI (erlotinib or gefitinib) at any time. The outcomes for these patients have not been reported, once again calling into question whether the use of erlotinib at some point is the critical factor for improved survival, or if use of this agent as maintenance therapy is key.
Conclusion
Given the most recent data with maintenance docetaxel, pemetrexed, and erlotinib, what should the current standard of care for the treatment of patients with advanced NSCLC? The use of these agents as maintenance therapy should be considered one of the standards, and the approval of pemetrexed in this setting by the FDA underscores this. The use of treatment breaks for patients following a response after first-line therapy should also be considered a standard of care. The implementation of either strategy must be individualized based upon the judgment of the treating physician and the wishes of the patient. The routine use of maintenance therapy in all patients will overtreat many patients who have indolent disease or durable responses to first-line therapy for whom a treatment holiday of many months is reasonable. The lack of use of maintenance therapy in all patients will result in a lost opportunity for some patients to receive these effective agents. These trials have investigated various novel treatment strategies in advanced NSCLC. Ultimately, the significant advances in outcomes for patients with advanced NSCLC will come from im proved therapeutics based upon a better understanding of the biology of the disease, and not from strategies that optimize modestly effective agents and typically result in a transient response lasting only a few months.
Discussion
Dr. Goss: What is the duration of "maintenance" therapy?
Dr. Fidias: In the docetaxel study, the median number was 6 cycles. This was considered acceptable because of the intensity of the regimen. But you have to consider that 50% of patients were able to receive 6 cycles of docetaxel in addition to 4 cycles of carboplatin and gemcitabine. For pemetrexed, treatment was continued until progression, and 20% were able to continue for 10 cycles.
Dr. Goss: In first-line therapy, we considered 4 cycles to be optimal. In the initial Shepherd study of docetaxel versus placebo in the second line, patients were treated continuously until progression, but the median number of cycles was 4. So the question is, if we are giving maintenance treatment, how many cycles do we give? Do we continue until progression, or is 4 enough?
Dr. Hanna: I rarely give maintenance, but I wouldn't give more in second line than in first line. You're dealing with more resistant cells. For chemotherapy I would give 4 cycles. For erlotinib, there's not the cumulative toxicity except for rash early on, and diarrhea sometimes waxes and wanes. You can give that until progression. If you give second-line chemotherapy, not maintenance, it's 4 cycles. There are those rare patients who derive a great deal of benefit and alleviation of symptoms, and for those I do prolong it a little bit, just because the duration of disease control is longer. And that has value even if they don't live longer.
Dr. Sequist: Because of the complexity of this topic, and the non-uniform practice around the country, this is going to have a ripple effect on future clinical trials. I think treatment is going to be disparate. Patients coming on clinical trials will have been on all kinds of "first-line" combination regimens, making the results very hard to interpret.
Dr. Lynch: I was very impressed with the overall outcome data for adenocarcinoma patients in the Belani trial. It dwarfs others studies. However, I don't think we know who benefits from maintenance. The trials that are available just don't help us. But even on the clinical studies, you can't select who will benefit and who will not.
Dr. Fidias: This is an issue that goes to the science. Who really benefits from early intervention? Are the patients who have a very good response, especially if they were symptomatic at the beginning, more likely to benefit? For patients who don't have a strong response to first-line therapy, you fear that at any time they may be progressing. But we don't have that data to be able to choose at this point.
Dr. Lynch: A big difference in the past 2 decades has been acceptance of first-line therapy at the time of diagnosis—not waiting. Today you treat pretty much everybody who is eligible for first-line—no watching and waiting.
Dr. Karp: We can't assume all treatment is good. Treatment may be harmful. We are trying to tailor treatment to provide optimal benefit for patients. This is the whole point of personalized care.
Dr. Lynch: Can you figure out who should get maintenance or early second-line?
Dr. Temel: I have actually begun offering maintenance chemotherapy to some of my patients. It is clearly not the best course of action for everyone and requires a detailed discussion with the patient. I tend to recommend it most strongly for people who are young and healthy, but who are so ill from their newly diagnosed metastatic disease that you are worried about getting them through first-line chemotherapy. For those patients who do well through first-line therapy and experience clinical benefit, I worry they will deteriorate quickly again if I defer second-line therapy and so consider maintenance therapy.
Dr. Evans: I have been using a lot of maintenance. I became accustomed to prolonged duration of pemetrexed in the relapsed disease setting where I saw it salvage some patients who had progressed through 2 or more lines of prior chemotherapy. I also did have some patients progress upon drug discontinuation and then respond again on reinitiation. I became very impressed with how people can tolerate it. Therefore, if patients are doing well and tolerating it, I tend to keep them on.