The historic standard for advanced NSCLC up until a few years ago was for patients to complete 4-6 cycles of platinum-based doublet chemo, and then for patients who were doing well and had responded or demonstrated stable disease to take a break from treatment and be followed until progression. At that point, many patients would re-initiate chemo or targeted therapy with an oral agent like Tarceva (erlotinib).
Part of the premise was that ongoing treatment with challenging chemotherapy generally led to cumulative side effects, and at the same time, the limited work that had been done on fixed duration vs. ongoing chemotherapy until progression failed to show a significant improvement in survival with prolonged chemo, though it was associated with increased side effects.
As more targeted agents came to be tested in combination with standard chemotherapy, the structure of the trials began to shift. Because these agents were generally developed with a premise that they had minimal or at most modest toxicity, the clinical studies often added new drug to 4-6 cycles of first line chemo, then continued the novel targeted therapy. Though this approach didn’t show a survival benefit when EGFR inhibitors like Iressa or Tarceva were added to chemo, and many other novel agents also failed to improve outcomes, this approach did show a significant improvement in survival with the anti-angiogenic agent Avastin (bevacizumab) added to first line chemotherapy, and it was approved by the FDA to be given with first line chemo and then continued as a maintenance therapy. However, the pivotal Avastin study doesn’t really address whether the combination with chemo, the maintenance component, or both are the key elements that produce the survival benefit. Many experts believe that the maintenance Avastin component adds little or nothing.
Meanwhile, Erbitux (cetuximab), a monoclonal antibody against EGFR, has also been shown to improve survival modestly but statistically significantly, also using a platform of doublet chemo with Erbitux, followed by maintenance Erbitux. This approach has not really been adopted because of the modest degree of improvement, added side effects with Erbitux, and the limitation that weekly IV administration is a real barrier, especially as an ongoing maintenance therapy.
Each of these examples describes continuation maintenance, which is when one or more agents from the first line setting are continued after a fixed duration of some portion of the initial chemotherapy. An alternate strategy is switch maintenance, which is when a new treatment is started immediately after a fixed duration of initial first line chemotherapy, typically 4-6 cycles, is completed.
Though early trials with this concept didn’t lead to much enthusiasm for this approach, many recent trials have shown a very consistent, highly significant improvement in progression-free survival with switch maintenance therapy using any of the more commonly used agents from the second line setting, namely Taxotere (docetaxel), Alimta (pemetrexed), or Tarceva (erlotinib). Less clear has been a survival benefit for giving these treatments as maintenance therapy as opposed to waiting until disease progression and initiating treatment after a break. Trials with both Alimta and Tarceva as switch maintenance have been positive by their statistical design and have shown a significant overall survival benefit, but these trials have had very significant design flaws that included only about 20% of patients on the placebo arms of these trials to receive the same or a similar drug later. In essence, this means that these trials were more clearly assessing the value of access to these agents at some point, more than the timing of whether they truly improve outcomes when given early vs. being administered later.
It is telling that an important trial of immediate Taxotere as switch maintenance therapy vs. delayed treatment with Taxotere at the time of progression, a design that best tested the timing of treatment rather than access to therapy, showed a highly significant improvement in progression-free survival but failed to show a significant improvement in overall survival (though it did show a strong trend in that direction).
What has been emerging is an increasing sense that these trials all reaffirm that these agents, of proven benefit in previously treated patients, are especially beneficial for patients who demonstrate a response or stable disease with first line chemotherapy. However, they can only be effective if a patient actually receives them, and one advantage of the maintenance therapy concept is that it provides a guarantee that patients most likely to benefit from subsequent treatment will receive that opportunity. However, there are not at this point any strong data to suggest that people who elect or are recommended to take a break from treatment and then are followed closely enough to initiate further treatment at the timely detection of progressing disease do any worse. In fact, there may be a benefit for many patients to have a break from treatment, and many patients who receive maintenance therapy will in essence be over-treated and would do just as well with a break from treatment.
In the end, the current evidence supports a very individualized approach to maintenance therapy that incorporates factors such as a person’s tolerance of treatment/need for time off, the degree of response to first line therapy, the remaining bulk of the cancer, the preferences of the patient, and other factors. Maintenance therapy is being increasingly considered and often recommended, but it isn’t a definitive standard of care for all eligible patients.
Finally, we really don’t have clear data to address which maintenance therapy to recommend. The concept of continuation vs. switch maintenance therapy was addressed in a French trial described thoroughly in several links below, but at this point any of several maintenance therapy, along with observation and good clinical and radiographic follow-up, are all appropriate considerations.
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