The PARAMOUNT trial1 represents an important landmark study of continuation maintenance therapy with pemetrexed (Alimta). While maintenance therapy gained a toehold in routine management of advanced non–small cell lung cancer (NSCLC) several years ago, the first trials that demonstrated a significant benefit for maintenance therapy employed a switch maintenance strategy. These trials were designed to switch patients to either pemetrexed in the JMEN trial2 or erlotinib (Tarceva) in the SATURN trial,3 with both demonstrating a significant improvement in progression-free and overall survival. (An underpowered trial demonstrated a significantly superior progression-free but not overall survival with early docetaxel after front-line gemicitabine/carboplatin.4) These trials led to pemetrexed and erlotinib each being approved as maintenance therapies for patients who hadn’t shown disease progression on first-line chemotherapy.
Like the JMEN trial, which randomly assigned patients without disease progression after four cycles of a nonpemetrexed platinum-based doublet 2:1 to pemetrexed or placebo, PARAMOUNT pursued the same randomization, but only after all patients had demonstrated a response or stable disease after four cycles of cisplatin/pemetrexed. As in the JMEN trial with pemetrexed as switch maintenance, we now know that continuation maintenance with pemetrexed is also associated with a statistically and clinically significant improvement in progression-free and overall survival.
Study Limitations
I consider these results to be impressive, but it’s also important to recognize that they don’t translate to a mandate to treat every eligible patient with maintenance therapy. Why not? Both the JMEN and SATURN trials suffered from (and also benefited from) a design that only administered the active drug at any time to about 80% of patients assigned to the placebo arm, thus compromising interpretation of the results—ie, the importance of maintenance therapy vs just receiving subsequent active therapy (or not). We therefore can’t know whether there is value in the timing of subsequent treatment or simply the access to it at all.
The positive results from the PARAMOUNT trial convincingly demonstrate a comparable efficacy for maintenance chemotherapy. We don’t have a directly comparative trial of continuation vs switch maintenance therapy, but the PARAMOUNT data look every bit as good as the results from switch maintenance trials.
The closest approximation we have available is the trial by Pérol et al,5 which randomly assigned patients who hadn’t shown progression after four cycles of cisplatin/gemcitabine to either continuation maintenance therapy with ongoing gemcitabine, switch maintenance erlotinib, or observation alone. Though not designed to directly compare continuation to switch maintenance therapy, the continuation maintenance therapy arm in the Pérol et al trial appeared numerically superior in the relative benefit in progression-free survival compared with observation alone, though neither arm demonstrated a significant improvement in overall survival.
Maximizing Benefit
One very important point of this work is that both the PARAMOUNT and Pérol et al studies clearly illustrate that patients who haven’t demonstrated progression through first-line treatment can continue to benefit from the nonplatinum component well beyond an initial four cycles if it is likely to be tolerated well on an ongoing basis. This is particularly true with agents demonstrated to confer a survival benefit in previously treated patients with advanced NSCLC.
However, this doesn’t mean that the treatment must necessarily be given immediately and without a break. There is no reason to believe that patients wouldn’t receive the exact same benefit if they resume a treatment like single-agent pemetrexed after a limited treatment break, whether that is defined as a fixed period of maybe 1 to 2 months or close follow-up with prompt reinitiation of treatment at an early sign of progression.
To me, the real advantage of a maintenance approach is that it is the most reliable way to ensure that a patient actually receives the maximal benefit from the treatments available. It’s possible for disease to progress faster than anticipated, with patients missing an opportunity to receive subsequent therapy, but that doesn’t happen with a maintenance approach. Nevertheless, a treatment break may still be a very acceptable choice for individual patients.
My personal view is that if continuation maintenance therapy is administered with an agent that is well-tolerated (as pemetrexed or, potentially, gemcitabine often is), then continuation maintenance therapy provides a way to maximize the benefit of further treatment without discarding a valuable therapy too early, and without initiating another treatment before it’s really needed. This is especially important because we don’t have an excess of treatments that remain effective in previously treated patients with advanced NSCLC.
In contrast, I would be more inclined to pursue switch maintenance therapy for people who haven’t shown progression and want, or are felt to need, maintenance therapy, but have experienced problematic, likely cumulative side effects from the first-line therapy.
Range of Options
Maintenance therapy has become an established standard of care in the past several years. However, this setting after first-line therapy is one in which there remains a range of viable options. Collectively, the key trials on maintenance therapy illustrate very clearly that there is a striking benefit for effective subsequent therapy in patients who have not had progression after first-line therapy.
Maintenance therapy strategies provide a reliable means for conferring that benefit, but there remains room for clinical judgment about whether an individual patient may be best served by continuation maintenance, switch maintenance, or a break from treatment. ■
Dr. West is Medical Director, Thoracic Oncology Program, Swedish Cancer Institute, Seattle.
Disclosure: Dr. West reported no potential conflicts of interest.
References
1. Paz-Ares L, de Marinis F, Dediu M, et al: PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol July 8, 2013 (early release online).
2. Ciuleanu T, Brodowicz T, Zielinski C, et al: Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer. Lancet 374:1432-1440, 2009.
3. Cappuzzo F, Ciuleanu T, Stelmakh L, et al: Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: A multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 11:521-529, 2010.
4. Fidias PM, Dakhil SR, Lyss AP, 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 27:591-598, 2009.
5. Pérol M, Chouaid C, Pérol D, et al: Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 30:3516-3524, 2012.
