Novel Agents in the
Treatment of Lung Cancer
New Approaches to First-Line Therapies
Challenging Existing Paradigms for Optimal First-line Treatment of Advanced NSCLC
In 1971, President Richard Nixon declared a broad "War on Cancer" and urged Americans to devote resources to find a cure. In 2009, President Barack Obama issued a remarkably similar call, asking for a "cure for cancer in our time." As we look at the outcome for metastatic non–small cell lung cancer (NSCLC), we see that the progress since 1971 has been steady but overall is still modest. The 5-year survival rate for all cases of lung cancer in 1971 was 10%, and in 2009 it stands at 15%. Much of that advance is due to better surgery and an improved ability to deliver local therapy. Part of this progress is due to adjuvant and neoadjuvant therapy for resectable lung cancer, and finally, some is attributable to combined-modality therapy for locally advanced disease. Until very recently, advances in therapy for metastatic disease have contributed little to the overall outcome for this disease.
Targeted Antibody Therapy with Chemotherapy
Monoclonal antibodies such as bevacizumab, directed against vascular endothelial growth factor (VEGF), and cetuximab, to the epidermal growth factor receptor (EGFR), are the first new drugs to improve outcome when added to a standard platinum-based 2-drug combination to treat advanced disease.
In the landmark ECOG (Eastern Cooperative Oncology Group) 4599 study, bevacizumab prolonged median survival from 10.3 months to 12.3 months in Stage IV patients with nonsquamous cell carcinoma.1 In 2009, we learned that patients who have treated brain metastases and those requiring anticoagulation can safely be treated with this agent.2 These patients had been excluded from the pivotal phase III study due to concerns about safety, mainly bleeding risk. It is still not prudent to use bevacizumab for patients with squamous cell cancer or those who have evidence of hemoptysis. Unanswered questions about this agent focus on the optimal chemotherapy regimen and the duration of therapy with bevacizumab—notably, is there benefit to continuing treatment after 4 cycles of chemotherapy? This question is particularly noteworthy with the advent of maintenance therapy using pemetrexed or erlotinib. The duration of therapy with bevacizumab will be addressed in a planned ECOG study.
Cetuximab is the second monoclonal antibody to show promise in advanced NSCLC. The FLEX study demonstrated a modest survival benefit of this drug when added to cisplatin/vinorelbine.3 The 099 study, using a carboplatin/paclitaxel backbone, failed to show either a progression-free survival (PFS) or overall survival (OS) benefit but did show an improved response rate.4 Quite simply, this is a drug that is begging for a biomarker to identify patients who are most likely to benefit from treatment. Unfortunately, in 2009 we learned of data from both of the large randomized trials that failed to show any usefulness of EGFR analysis (copy number, immunohistochemistry, or mutation) or ras mutation status. Without a way to identify patients who might benefit (or those who might be harmed), it is unclear how to incorporate this drug into the treatment paradigms.
Maintenance Therapy
In 2009 the U.S. Food and Drug Administration (FDA) approved a new type of therapy for advanced NSCLC: maintenance therapy. Called maintenance by some, early second-line or consolidation by others, the use of single-agent chemotherapy beyond the initial 4 cycles was the basis for the FDA extension of the label for pemetrexed. The pivotal study showed a dramatic prolongation of survival from 10 months to 15 months in patients with nonsquamous cell cancer who received maintenance pemetrexed following non-progression on 4 cycles of platinum-based therapy.5 Of note, the platinum-based treatment did not include pemetrexed with platinum, so it is not clear if this option provides a similar benefit for those patients who receive upfront pemetrexed. The pivotal study is consistent with the Scagliotti study of first-line pemetrexed6 and the Hanna study comparing pemetrexed to docetaxel in that benefit is limited to those patients who have nonsquamous cell carcinoma.7
Pemetrexed is not the only treatment to show benefit when used earlier in the course of therapy. EGFR-based treatment with erlotinib also appears to have benefit in the maintenance setting. The SATURN study randomized patients after 4 cycles of platinum-based treatment to receive either erlotinib or placebo.8 A benefit in OS and PFS was seen for both adenocarcinoma and squamous cell carcinoma. When bevacizumab-based therapy was used, the ATLAS study showed a PFS benefit for erlotinib given in the maintenance phase of treatment.9
Many thoughtful oncologists have examined the maintenance data and have questioned the adequacy of second-line therapy in the groups of patients that did not receive maintenance. For trials such as JMEM, nearly 40% of the patients on the control arm did not receive any second-line therapy. This has led some to believe that if second-line can be administered aggressively, a treatment break after first-line therapy is certainly reasonable. However, it is not clear if we are skilled enough as clinicians to predict which patients "fall off" and do not receive second-line therapy. The data for pemetrexed in particular are impressive and may well represent a significant paradigm change for patients with nonsquamous cell carcinoma.
Patient Selection
The IPASS study, published in 2009 in the New England Journal of Medicine, is arguably the most important study done in advanced lung cancer over the past decade.10 This trial demonstrated a clear PFS and quality-of-life benefit to the use of first-line gefitinib compared to chemotherapy in patients with EGFR activating mutations. Most important is the finding that clinical criteria are insufficient to select patients for therapy. If a never-smoking Asian woman who is EGFR wild-type presents with Stage IV NSCLC, use of gefitinib is significantly worse than chemotherapy. First-line EGFR tyrosine kinase inhibitors (TKIs) should be restricted to patients who have a clear EGFR mutation. The IPASS study provides support for a randomized phase III trial based on the many phase II studies from US, Europe, and Asia of first-line TKIs in mutation-positive patients. Future advances in lung cancer treatment will involve molecular profiling of tumors to unveil additional targets. An example of this is the recently described EML4-ALK fusion protein, which is seen in approximately 4-10% of patients and appears in initial studies to be sensitive to a combined Met/ALK inhibitor.11
Up-Front Supportive Care and Brain Metastasis
Patients who present with brain metastases from NSCLC represent a unique and important subgroup. Prior approaches involving whole-brain radiation delivered at the dose of 30 Gy over 10 days might be acceptable if OS is in the range of 6 months. However, now that we have patients living longer than 1 year (or in the case of EGFR mutations, 2 years), how we manage brain metastases is dramatically more critical. Some oncologists advocate local therapy alone—either surgery or stereotactic radiation therapy— and defer whole-brain radiation until there is evidence of multiple sites of disease progression. Others feel that systemic chemotherapy or EGFR TKIs can begin even before the central nervous sysytem (CNS) disease is treated. Both of these approaches represent new paradigms in treating advanced disease.
Despite all of the advances discussed above, 98% of patients who have Stage IV NSCLC will die from their disease, the vast majority within 2 years of diagnosis. How we care for patients at end of life speaks volumes about our compassion as caregivers. An important trial randomizing patients to either standard palliative care or the experimental arm of palliative care at diagnosis is shedding light on the key role that end-of-life care plays and how illness is perceived by the patient and family. Realistic discussion of disease prognosis is also critical in order to allow patients to make informed decisions. Emerging data show that lung cancer patients are not harmed by frank disclosure of prognosis, and in fact are likely to use this information to make better decisions about future care.
This activity brings together the perspectives of many of the experts working in all aspects of treatment for advanced-stage NSCLC. Since lung cancer is the leading cause of cancer death in the world, treatments that help even small populations of patients can have a significant impact on many individuals. As you review this CME activity, consider how you can implement this information into your practice, whether it be in assessment, counseling, treatment, management, and/or accessing more information.
You will have an opportunity to access the case study activity following your completion of this activity, or you can access it directly at http://www.informedicalcme.com/1stcases.