New Lung Cancer Treatment Approach Raises Hopes and Debate
A number of clinical trials have tried and failed to improve survival in patients who have advanced non-small cell lung cancer (NSCLC) by extending the duration of their initial treatment. The premise behind the approach, often called maintenance therapy, is simple: In patients whose tumors regress following their initial treatment, give the cancer another kick while it's down, rather than waiting for it to regain steam before delivering further therapy.
Where past trials have failed, though, several recent phase III trials using more current agents have reported some success using maintenance therapy. To date, one trial has reported improved overall survival and a second, the SATURN trial, is slated to report improved overall survival next week at an international lung cancer conference. Several other trials have shown improvements in progression-free survival. Among patients with advanced disease, for whom survival can range from a few months to 1 or 2 years, any improvement is good news.
Positive Trials of Maintenance Therapy in NSCLC
|Phase III Clinical Trials||Findings|
|Maintenance pemetrexed versus best supportive care (663 patients)||Improved overall survival (OS) (15.5 versus 10.3 months, nonsquamous only) and progression-free survival (PFS)|
|Immediate versus delayed docetaxel (309 patients)||Improved PFS (5.7 versus 2.7 months) with a trend toward improved OS, but not statistically significant|
|SATURN - Maintenance erlotinib versus best supportive care (889 patients)||Slight improvement in PFS (12.3 weeks versus 11.1 weeks), with OS data to be reported on August 1|
|ATLAS - Erlotinib and bevacizumab maintenance therapy versus bevacizumab maintenance therapy (768 patients)||Slight improvement in PFS of approximately 1 month|
Even with the positive data, though, leading lung cancer experts disagree on some important details about precisely how maintenance therapy fits into the current treatment mix for advanced NSCLC, which now includes numerous options for first-, second-, and third-line treatments, some of which are targeted therapies.
The debate over maintenance chemotherapy has taken on renewed importance in recent weeks, with the FDA's approval of the first agent for use in this indication, pemetrexed (Alimta). Just how deeply this new treatment approach will reach into the clinic is unclear. According to Dr. Sherman Baker, Jr., of Virginia Commonwealth University's Massey Cancer Center, it's already being done on a limited basis and its use is now likely to expand.
"The question in my mind is, will we do it right?" he said. That is, will clinicians follow the approaches that clinical trials have shown offer a benefit? Dr. Baker also wonders if these trials will alter cancer specialists' mindset. "Will these trials change how we view advanced NSCLC—not just as a disease that is always fatal but as something that we may be able to make more of a chronic disease, where 2-year survivals are more common?"
This diagram of stage IIIA non-small cell lung cancer shows cancer in the lymph nodes, left main bronchus, pleura, diaphragm, and chest wall.
Getting to this Moment
Although there is some disagreement on the role of maintenance therapy, there is no question about the duration of first-line chemotherapy in patients with advanced NSCLC—four to six cycles (most often four)—or that first-line chemotherapy should consist of a combination of agents that include a platinum chemotherapy drug such as cisplatin or carboplatin. Numerous trials have shown that these platinum-based "doublets" are highly effective, but that going beyond six cycles simply piles on toxicity without any added clinical benefit.
Maintenance therapy—as practiced in the phase III clinical trials that have reported positive results (see sidebar)—comes into play in patients whose tumors have responded to first-line therapy. These patients then immediately begin treatment with maintenance agents until their disease shows signs of progressing.
In the international phase III trial that garnered pemetrexed's FDA approval for this new indication, patients with advanced NSCLC of the nonsquamous type had a median overall survival of 15.5 months with pemetrexed maintenance therapy, compared with 10.3 months for those who received best supportive care. Progression-free survival also improved significantly. Patients with squamous cell carcinoma did not benefit from the maintenance therapy regimen.
Dr. Chandra P. Belani, the trial's principal investigator, believes the trial results establish maintenance therapy as a new standard of care for nonsquamous NSCLC. "Such a survival benefit with maintenance therapy has not been seen before," he said. Given the low rate of less-severe side effects seen with pemetrexed, he added, the potential survival benefits warrant its use.
"Whenever there is something new, there are going to be those who are reluctant to use it," Dr. Belani said. "But now that it is approved [by the FDA] based on the trial results, how can you deny it to patients?"
Dr. Nasser Hanna, from Indiana University's Simon Cancer Center, remains skeptical of maintenance chemotherapy for most patients with advanced NSCLC. The survival benefit in the pemetrexed trial, he argued, is not quite what it seems because many patients in the trial's non-maintenance arm did not receive the study drug or any approved second-line therapy once their disease progressed. And even low-grade toxicities, he added, "are not trivial," particularly in this patient population.
Similar results, Dr. Hanna continued, can be achieved in many patients even if they get a "holiday" from treatment—referring to the practice of giving patients time to recover from the duress of first-line treatment—or even if, as current guidelines recommend, the next round of treatment is not initiated until there are signs of progression.
In another positive maintenance therapy trial that used the chemotherapy drug docetaxel (Taxotere), published earlier this year, a significant percentage of patients in the non-maintenance arm did not receive docetaxel upon disease progression. However, patients who did had the same survival as those who received it immediately.
"I don't see these trials as demonstrating that maintenance therapy is necessary for the majority of patients," Dr. Hanna said. "But they do underscore the value of these agents in metastatic disease and the importance of not losing the opportunity to treat patients with these drugs."
That limited window of opportunity, argued Dr. Belani, is exactly why immediate administration of therapy is so important. "There is no way to predict which patient will benefit from a treatment holiday," he said. "After a treatment holiday, a third of patients can't go on to [receive the next] treatment. They either have a declining performance status, their cancer progresses, or they die."
No Longer "One and Done"
A key point to take away from the recent positive maintenance therapy trials is that they all involved FDA-approved second- and third-line treatments, said Dr. Mark Socinski from the University of North Carolina's Lineberger Comprehensive Cancer Center. This is a big change from earlier in this decade, he noted, when there were fewer effective first-line therapies for NSCLC, let alone anything beyond that.
"These trials are telling us that it's important for patients to get drugs known to improve survival," he said. "A maintenance strategy is one way to do that." Regardless of the strategy that's chosen, Dr. Socinski continued, the available data indicate that oncologists need to more closely consider the next line of therapy and educate their patients about it.
"We need to tell them, if your cough gets worse, if the pain gets worse, don't wait for your next appointment. Don't ignore your symptoms," he said. "Patients need to hear that something like that means their disease might be getting worse, and they need to know that getting active agents can help."