Does Maintenance Therapy Improve Survival in NSCLC?

One of the common assumptions in oncology treatment is that earlier detection and treatment is better and leads to improved survival and outcomes for patients, but does this hold true in reality? The big theme for this ASCO meeting has been personalizing cancer therapy and looking at ways oncologists can apply the existing body of knowledge

Typically, advanced lung cancer patients get four, sometimes six cycles of chemotherapy and are then monitored until progression, whereupon another therapy is tried. The big question raised recently is whether adding a new treatment or combination of drugs as maintenance therapy would improve overall survival. A number of trials presented at the ASCO annual meeting attempted to answer this important question.

An entire session was devoted to answering the question of whether using therapies sooner after chemotherapy would lead to better results in patients with advanced lung cancer than delaying treatment until after signs of disease progression on chemotherapy. Data were presented on pemetrexed (Alimta), erlotinib (Tarceva), and bevacizumab (Avastin) in the early treatment of advanced non-small cell lung cancer (NSCLC). The goal of these studies is to see whether these agents improve clinical benefit and lead to a better quality of life for patients.

Efficacy of Pemetrexed as Maintenance Therapy in Advanced Lung Cancer

In this study, 663 patients with metastatic lung cancer were randomized 2:1 to receive pemetrexed or best supportive care (placebo) after initiation with standard chemotherapy. There were no differences between the groups in terms of baseline characteristics. The primary end points were progression free survival (PFS), and secondary endpoints were overall survival (OS), overall response rate (ORR), overall clinical response (OCR), safety, and tolerability.

The most common chemotherapies chosen were gemcitabine (Gemzar) plus carboplatin or cisplatin. In the pemetrexed arm, 48% of patients received six cycles of chemotherapy compared with 28% of patients in the placebo arm.

The ORR was 3.4% in the pemetrexed arm and only 0.5% in the placebo arm. With regard to PFS, data showed the following, which is broken out by histology:

Pemetrexed Placebo

Overall 4.0 mo 2 .0 mo

Nonsquamous 4.4 mo 1.8 mo

Squamous 2.4 mo 2.5 mo

Clearly, there was significant benefit for patients with tumors of nonsquamous histology, and no benefit for patients with squamous cell NSCLC.

Preliminary OS results showed a similar trend: patients who took the drug lived 26% longer compared with the control group:

Pemetrexed Placebo

Overall 10.6 mo 13.4 mo

Nonsquamous 15.5 mo 10.3 mo

Squamous 9.9 mo 10.8 mo

Belani, the lead author and presenter, said, “Maintenance therapy with Alimta offers a new paradigm for patients who have advanced lung cancer, because it has a low toxicity and can be given on an ongoing basis over a prolonged period of time to extend patients' lives.”

Efficacy of Erlotinib as Maintenance Therapy in Lung Cancer

Two studies attempted to address the question of whether erlotinib was effective if given shortly after standard first-line chemotherapy for lung cancer. One study (n = 889) looked at erlotinib as a single agent, and the second examined the combination of erlotinib and bevacizumab in patients with nonsquamous histology.

The final results of the SATURN trial demonstrated that erlotinib significantly improved PFS in chemotherapy-naive patients with both squamous and nonsquamous cell lung carcinoma by 41% compared with placebo. Patients with an endothelial growth factor receptor (EGFR) mutation achieved a 10-fold increase in the time they survived without their disease worsening. The biomarker data suggest that KRAS mutation status is not a predictor of efficacy in patients with NSCLC treated with erlotinib, as had been hoped.

The second trial, ATLAS, looked at the combination of erlotinib with bevacizumab as maintenance therapy following a first-line regimen of standard chemotherapy versus bevacizumab monotherapy in abou 750 patients with nonsquamous histology. Patients treated with the erlotinib-bevacizumab combination saw their cancer growth slow more than those in the control group treated with bevacizumab alone.

Patients were randomized to receive bevacizumab plus placebo or bevacizumab plus erlotinib. Those in the erlotinib group survived an average of 4.8 months before the cancer started growing again, compared with 3.7 months for patients in the control group. This translates to a 29% reduced risk of disease progression for patients who took the erlotinib and bevacizumab combination compared with bevacizumab alone.

Presenter Vincent Miller, MD, observed, “This is the first study to show that adding erlotinib to maintenance therapy with bevacizumab delays disease progression in patients who have already received bevacizumab as part of their initial chemotherapy.”

While these results are a step in the right direction, the discussant, Nasser Hanna, Indiana University, pointed out that patients ask whether they will live longer and feel better. Hanna observed that all three therapies add more grade 3 and 4 toxicities and even grade 1/2 events are not trivial. OS has not yet been demonstrated in the erlotinib trials (the data is expected by the end of 2009) and in fact, several prior phase II trials (eg, FASTACT and BETA) with erlotinib and bevacizumab have demonstrated an improved PFS, but in the final analysis, median OS was not significantly impacted. He also stated that it is not clear that earlier treatment leads to “patients living longer and experiencing decreased cancer symptoms, fewer complications from their cancer and improved quality of life. None of that has been demonstrated with these studies.”