Evidence for Early Second-line Therapy: Pemetrexed

Pemetrexed

Pemetrexed is an antifolate that inhibits thymidylate synthase, along with other enzymes involved in purine and pyrimidine synthesis.³⁷ Pemetrexed was FDA-approved in patients with previously treated NSCLC after a phase III trial reported similar outcomes and better tolerability when compared to docetaxel in the second-line setting.³⁸ More recently, in a trial published by Scagliotti et al, pemetrexed plus cisplatin was compared with gemcitabine plus cisplatin in the first-line setting. Overall, patients had comparable outcomes in the two arms, with no statistical difference in survival.⁷ The pemetrexed-containing regimen, however, did exhibit a more favorable safety profile compared with the gemcitabine-containing regimen. Based on these results, pemetrexed is now approved by the FDA in the first-line setting in combination with cisplatin for treatment of advanced nonsquamous NSCLC. In addition, because pemetrexed is active, relatively convenient to administer, and generally well tolerated, it was evaluated in maintenance and consolidation protocols following first-line treatment. Based on the results of those studies, which are described below, in June 2009 pemetrexed was approved for maintenance therapy in NSCLC following 4 cycles of platinum-based therapy.

Maintenance Pemetrexed

At the 2009 ASCO meeting, Belani et al reported results from a phase III trial evaluating maintenance pemetrexed in patients with advanced NSCLC.⁴ Patients who had not progressed on 4 cycles of platinum-based chemotherapy were randomized to receive either pemetrexed (n = 441) or placebo (n = 222) in 21-day cycles until disease progression. Investigator assessment of PFS was the primary end point of the study. Patient characteristics were well balanced with respect to sex, age, histology, PS, smoking history, and best response to induction therapy. The authors reported that patients on the pemetrexed arm had significantly better OS, PFS, and response compared to placebo (Table 1). The improvements in PFS and OS were observed primarily in patients with nonsquamous histology. Treatment by histology interaction for OS was significant (P = 0.038). Pemetrexed therapy was associated with higher rates of grade 3/4 adverse events than placebo (16% vs 4%, P < 0.001). Patients receiving pemetrexed experienced more significant fatigue (5% vs 0.5%) and neutropenia (2.9% vs. 0%).

(click table to view larger version)

Nonsquamous histology

Over the past 2 years, new information has emerged indicating that pemetrexed is significantly more active against nonsquamous NSCLC compared with squamous tumors. A retrospective analysis by Peterson et al indicated that pemetrexed treatment resulted in improved survival in nonsquamous tumors in the second-line setting.³⁹ Patients with nonsquamous histology had a median OS of 9.3 months when treated with pemetrexed compared with 8 months on the docetaxel arm (HR = 0.778, P = 0.048). The opposite was true, however, for those with squamous histology, for which median OS was better with docetaxel (7.4 versus 6.2 months, HR = 1.563, P = 0.018). Similar findings were reported in a first-line study by Scagliotti et al in which chemo naive patients with advanced NSCLC were randomized to treatment with cisplatin/gemcitabine or cisplatin/pemetrexed.⁷ In that trial, patients with nonsquamous histology had a statistically significant improvement in OS on the pemetrexed arm compared with those on the gemcitabine arm (Figure 1). The largest benefit with pemetrexed was seen in patients with large cell carcinoma (OS 10.4 versus 6.7 months). In contrast, those with squamous histology survived longer on the cisplatin/gemcitabine combination arm (OS 10.8 versus 9.4 months). The importance of histology was also confirmed by Belani et al as presented above.

(click table to view larger version)

(click table to view larger version)

The trial by Belani et al raises several interesting questions.

• Should the immediate use of pemetrexed follow first-line therapy in all patients prior to disease progression? We believe the answer is still no. Clearly, those patients with squamous cell histology should not receive maintenance pemetrexed. Given that 28% of patients on the placebo arm received 6 cycles of placebo, it is also apparent that not all patients require immediate second line therapy, as some achieve disease control for 3-6 months with first-line chemotherapy. Other patients will have more indolent cancer growth.
• What is the value of improved PFS in the absence of improved quality of life? None of the maintenance trials show an improvement in QoL. At the 2008 ASCO annual meeting, Zielinski et al presented patient-reported outcomes from the Belani et al trial, which were measured using the LCSS.⁴⁰ The improved PFS seen on the pemetrexed arm did not appear to translate into an improved QoL. This requires a balance of accepting treatment toxicity, albeit low, with the benefits of reducing cancer symptoms. For patients with minimal cancer symptoms (pain, weight loss, etc.), the tradeoff is likely not worthwhile.
• Does the use of a placebo control arm in which only 19% of patients eventually received pemetrexed therapy affect the interpretation of overall survival results? While this study confirms the activity of pemetrexed in nonsquamous histology, it does not support the routine use of maintenance chemotherapy.

Conclusion: Early Second-line Therapy

In summary, recent trials have consistently shown a PFS advantage for early therapy, with a statistically significant improvement in OS for pemetrexed, which were especially impressive for the nonsquamous cell subtypes. Whether these results are applicable to patients receiving upfront pemetrexed is unclear. The hazard ratios for PFS and OS are essentially identical between the docetaxel and pemetrexed trials, raising the possibility that an "early switch" to a non-cross-resistant regimen is more important than the regimen itself. In terms of early second-line erlotinib, whether PFS differences alone should be practice-changing clearly depends on the magnitude of the benefit, the toxicities of the regimen, and the global QoL of the patients, as well as the cost of therapy. It continues to be our practice at Indiana University to offer most patients a treatment break following a response to first-line therapy. Treatment breaks allow patients to recover from acute toxicities and to restore some normalcy to their lives, with fewer physician visits and less time spent in the infusion center. Nevertheless, these and other trial results clearly indicate that it is very important to offer eligible patients second-line therapy. Giving patients a treatment break, therefore, requires very close follow-up to minimize losing the opportunity for second-line therapy in patients who may develop rapid clinical deterioration or other complications that preclude additional therapy.

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