Top Stories of 2012: Changing Approach to Advanced NSCLC: Focus on Pemetrexed Maintenance Therapy and Predictive Biomarkers

To mark 2012, we have asked our PracticeUpdate Advisory Board Members to choose their top story of the year. In this interview, Dr. Jean-Yves Douillard discusses his choice for this year in lung cancer.

PracticeUpdate: In your view, which development in oncology research that occurred in 2012 could have the most significant impact on lung cancer?

Dr. Douillard: During 2012, several clinical trials were reported at various meetings, including the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), and the International Association for the Study of Lung Cancer (IASLC). The issue of maintenance treatment after induction chemotherapy was addressed in two large randomized trials.

First, the final results of the PARAMOUNT trial were presented at ASCO 2012 by Dr. Luis Paz-Ares. Overall survival (OS) was improved with maintenance pemetrexed after an induction regimen of pemetrexed and cisplatin. The use of maintenance pemetrexed reduced the risk of death by 22%, at a significant P value. A benefit in progression-free survival (PFS), with a reduced risk of 38%, had been previously reported. These data definitively establish maintenance therapy with pemetrexed as a possible standard of care in patients with stage IV nonsquamous non–small cell lung cancer (NSCLC).

Second, the POINTBREAK study was presented by Dr. Jyoti D. Patel at the 2012 IASLC meeting. This study of nonsquamous stage IV NSCLC compared the US standard treatment of paclitaxel, carboplatin, and bevacizumab followed by bevacizumab maintenance therapy with an induction regimen of pemetrexed, carboplatin, and bevacizumab followed by pemetrexed and bevacizumab maintenance therapy. The primary endpoint of an OS benefit was not met (HR, 1). PFS was slightly and significantly improved (P = .012; HR, 0.83).

These two trials have important clinical practice implications. They addressed the same patient population. The PARAMOUNT study showed that pemetrexed maintenance therapy improved OS from both induction and randomization; the POINTBREAK study showed that the addition of bevacizumab to pemetrexed and carboplatin (as opposed to cisplatin in the PARAMOUNT trial) did not improve OS as compared with the US standard treatment. A cross-trial comparison is hazardous, but the numerical values of median OS and the magnitude of the benefit of the hazard ratio favor the PARAMOUNT approach.

Other important results presented in 2012 focused on the continued development of personalized medicine based on predictive biomarkers.

Presented by Dr. James Yang at ASCO 2012, the LUX-Lung 3 study compared afatinib with pemetrexed and cisplatin in the first-line treatment of EGFR-mutant (all mutation types) NSCLC. The results showed an improvement in PFS (HR, 0.58) and response rate (RR) in favor of afatinib. The OS data were not mature enough to be presented.

Presented by Dr. Alice Shaw at ESMO 2012, the PROFILE 1007 study compared second-line chemotherapy (pemetrexed or docetaxel) with crizotinib in ALK-positive patients. The results showed an improved RR (65% vs 20%) and PFS (HR, 0.49). No OS data were provided.

Finally, in a single-arm trial, patients with EGFR-mutant NSCLC were pretreated with either erlotinib or gefitinib and rechallenged with the second-generation TKI afatinib plus the anti-EGFR monoclonal antibody cetuximab. Resistance to the EGFR TKI was reversed, with a RR of 30%, including in patients with so-called resistance T790M mutation. These data illustrate the need to identify patients with predictive biomarkers to provide them with the appropriately targeted agent.

PracticeUpdate: What specific changes in oncology have you observed or do you foresee as a result of this development?

Dr. Douillard: From my point of view, maintenance chemotherapy with pemetrexed is an established approach and should be used in patients with disease controlled after induction chemotherapy. From the comparative analysis of the PARAMOUNT and POINTBREAK studies, the role of bevacizumab is still unclear, considering the added potential toxicity and cost.

Personalized medicine is offering new treatment options in select patients. Screening for genetic mutations or other predictive biomarkers when drugs are available should be enforced.

PracticeUpdate: Would you put this development into historical perspective for the practicing oncologist?

Dr. Douillard: The most spectacular development with a totally different approach than chemotherapy is in the field of personalized medicine, and it should enter routine clinical practice after appropriate biomarker screening. However, platinum-based chemotherapy remains the cornerstone of treatment in the majority of cases where no predictive biomarker is detected. Treatment choices should be guided based on histology, keeping in mind the limitation of tissue available and the reliability of the histotype on a small biopsy specimen.

PracticeUpdate: Would you sum up in a single sentence why you chose these developments as the top story of the past year?

Dr. Douillard: They indicate a change in the management of stage IV NSCLC, with a need to include biomarker screening in the initial workup to guide the decision on the use of a targeted therapy or a conventional histology-guided platinum-based treatment when no biomarkers have been identified.