ResourcesMiami Lung Cancer Conference™ Medical Crossfire®
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Miami Lung Cancer Conference™ Medical Crossfire® is a nationally recognized health care communications platform dedicated to improving medical practices and patient care through debate, discussion, and authoritative peer-exchange on important clinical issues. This installment of Medical Crossfire® will include three panel discussions: panel one is focused on the role of antibodies and maintenance therapy in advanced disease, panel two is focused on EGFR and ALK, and the final panel will focus on immunotherapy. This discussion will be structured around specific questions relevant to issues faced by practicing community oncologists.
PER Pulse™ Recap
Three PER Pulse™ Recaps presenting key topics from the 1st Annual Miami Lung Cancer Conference™, which was held on March 8, 2014.
PER Pulse™ Recap
Medical Writer: Kelly McCoy Haden, PhD
Medical Crossfire® is a nationally recognized health care communications platform dedicated to improving medical practices and patient care through debate, discussion, and authoritative peer-exchange on important clinical issues. Medical Crossfire® is based on the understanding that exposure to differing -- and sometimes controversial -- opinions, insights, and philosophies fuels learning and understanding among health care professionals. This is the first in a series of three PER Pulse™ Recaps summarizing highlights of the 2014 Miami Lung Cancer Conference™: Medical Crossfire®.
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PER Pulse™ Recap
In the first panel, activity chair Dr. Thomas Lynch was joined by expert panelists Drs. Edward S. Kim, Rogerio C. Lilenbaum, and David R. Spigel for a discussion of traditional therapies for patients with advanced NSCLC. Highlights included:
Evolving paradigms with regard to antiangiogenic therapy for EGFR-, KRAS-, ALK-, and ROS1-rearrangement-negative metastatic adenocarcinoma of the lung. Although the landmark E4599 trial showed that the addition of bevacizumab to first-line carboplatin/paclitaxel significantly prolonged overall survival (OS) compared with chemotherapy alone in nonsquamous NSCLC, and subsequent trials have confirmed a progression-free survival (PFS) benefit, initial excitement has waned. This may be in part due to the favorable safety profiles of newer pemetrexed-based regimens, and the lack of a biomarker to help select patients who will derive benefit from bevacizumab, making it difficult to weigh the risk-to-benefit ratio of antiangiogenic therapy in individual patients. However, recent positive findings with the anti-vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody ramucirumab have renewed excitement. The randomized, phase III REVEL trial of patients previously treated with bevacizumab reported improved OS and PFS when ramucirumab was added to second-line docetaxel in patients with both squamous and nonsquamous NSCLC. Although guardedly optimistic about these results, the panelists agreed that mature data are necessary before changing practice patterns.
Treatment strategies in elderly and PS 2 patients with NSCLC. Dr. Lilenbaum noted that only a minority of elderly patients receive evidence-based treatment for NSCLC, but emphasized that being elderly does not necessarily equate with a PS of 2. Phase III data have now established that platinum doublet chemotherapy significantly prolongs OS over single-agent chemotherapy in elderly patients, without a substantial increase in toxicity. An exception were the "old elderly," who are ≥75 years-old and did experience more toxicity. The panelists agreed that physicians should try to give elderly patients a combination regimen, rather than single-agent chemotherapy or erlotinib, but acknowledged that age becomes an increasingly important consideration for patients ≥80 years. Further, clinical data suggest that patients with a PS of 2 also have better survival outcomes with combination chemotherapy (eg, carboplatin/pemetrexed) than with single-agent chemotherapy (pemetrexed). However, these gains do come at the cost of increased toxicity.
Maintenance therapy in NSCLC. Based on currently available data, experts agreed that either maintenance therapy (continuous or switch) or close observation are reasonable options for patients with nonprogressing NSCLC after first-line therapy. Evidence supporting continuation maintenance comes from the E4599 and PARAMOUNT clinical trials, which showed that administering bevacizumab and pemetrexed, respectively, until progression, improved survival outcomes. With respect to switch maintenance, the Fidias switch trial reported that after platinum-based chemotherapy, docetaxel maintenance therapy significantly prolonged PFS compared with second-line docetaxel. Positive findings also were reported in the SATURN trial, which demonstrated a significant PFS and OS benefit with erlotinib switch maintenance therapy versus placebo in NSCLC, including patients with wild-type EGFR. Two ongoing trials are further evaluating maintenance strategies. The first is a phase III trial in which maintenance nab-paclitaxel will be continued after first-line carboplatin/nab-paclitaxel in squamous NSCLC. The second is the ECOG 5508 trial, in which first-line carboplatin/paclitaxel/bevacizumab will be followed by maintenance bevacizumab, pemetrexed, or bevacizumab/pemetrexed in nonsquamous NSCLC. Findings from these trials have the potential shape the use of maintenance therapy in NSCLC.
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PER Pulse™ Recap
In the second panel, activity chair Dr. Thomas Lynch was joined by expert panelists Drs. Balazs Halmos, Gregory Riely, and Sarah B. Goldberg for a discussion about the management of patients with advanced non-small cell lung cancer (NSCLC). Highlights included:
EGFR-targeted therapies and testing in metastatic NSCLC. Although EGFR tyrosine kinase inhibitors (TKIs) were originally evaluated in all patients with metastatic NSCLC, it was soon discovered that their efficacy was mostly limited to patients with EGFR- activating mutations. Thus, guidelines now recommend widespread EGFR mutation testing in patients with nonsquamous, metastatic NSCLC. However, a limitation of EGFR testing is its turnaround time, which may require patients to wait 2 or more weeks to initiate therapy. While the use of EGFR testing and EGFR TKIs in metastatic disease has been established, the role of these tests and agents in stage I-III NSCLC remains investigational. Recent clinical trial data in early-stage disease appear promising with respect to disease-free survival in patients with EGFR-activating mutations. However, the panelists mostly agree that more data are necessary before changing practice patterns.
ALK-directed therapies in metastatic NSCLC. The discovery of the EML4-ALK fusion gene in NSCLC was followed by the approval of crizotinib, an ALK TKI that significantly extended progression-free survival relative to conventional chemotherapy in patients with NSCLC. Notably, EML4-ALK rearrangements tend to only occur in the absence of EGFR and/or KRAS mutations, suggesting that ALK testing may be unnecessary in EGFR and/or KRAS mutation-positive NSCLC. Detection of the EML4-ALK fusion gene currently requires an assay based on fluorescence in situ hybridization (FISH), which has a long turnaround time, but other techniques, such as immunohistochemistry, are under investigation. Upon detecting the EML4-ALK fusion gene in a patient with advanced NSCLC, the panelists tend to use crizotinib over platinum-based doublet chemotherapy, and may even continue its use beyond progression in indolent and/or asymptomatic disease. In addition, several second-generation ALK inhibitors (eg, ceritinib*, alectinib) are currently under investigation, some of which have demonstrated promising clinical activity, even in patients previously treated with crizotinib.
- Overcoming resistance to EGFR- and ALK-targeted therapies in metastatic NSCLC. For patients with EGFR-activating mutations or the EML4-ALK fusion gene, the corresponding EGFR and ALK TKIs, respectively, have become standard of care. Nevertheless, resistance to these TKIs emerges within 1-2 years, and often sooner. In the case of resistance to EGFR TKIs, it may soon become necessary to rebiopsy patients to discern the responsible mechanisms (eg, secondary mutations, bypass pathways, histologic transformation, and/or others) because next-generation TKIs are being developed to overcome specific resistance mechanisms. Less is known about acquired resistance to ALK TKIs, and diverse resistance mechanisms have been identified. Fortunately, as mentioned above, second-generation ALK inhibitors have demonstrated antitumor activity in patients with advanced NSCLC, including those exposed to crizotinib and those with brain metastases. Given that these and other investigational EGFR and ALK TKIs have shown encouraging antitumor activity in early trials, mature data from phase III clinical trials are eagerly awaited.
*In the time that has passed since the panel convened, this agent has been granted FDA approval for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib
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PER Pulse™ Recap
In the third panel, activity chair Dr. Thomas Lynch was joined by expert panelists Drs. David R. Spigel, Leora Horn, and Abraham Schwarzberg for a discussion about the management of patients with advanced non-small cell lung cancer (NSCLC). Highlights included:
Rationale and Mechanisms of Immune-Based Therapies. Although some NSCLCs are highly sensitive to inhibition of a single pathway (eg, EGFR, ALK), many lung cancers contain no identifiable oncogenic driver. In particular, squamous NSCLCs are so "genetically complex," according to Dr. Spigel, that targeting a single pathway in these cancers has limited therapeutic utility. Therefore, leveraging the immune system to nonselectively destroy tumor cells may benefit patients with many types of lung cancer. Immunotherapies like interleukin-2 historically were used to treat certain cancers but came at the expense of substantial toxicity. Newer, investigational immonotherapies began to garner excitement when they demonstrated encouraging clinical activity and a more tolerable safety profile. In particular, therapies have been developed to block the immune system's "checkpoint" pathways that tumors hijack in order to avoid destruction. For example, antibodies targeting the programmed cell death-1 (PD-1) receptor or its ligand, PD-L1, reinstate the immune system's ability to recognize and destroy tumors. These and other immunotherapies (eg, ipilimumab, vaccines) have elicited responses in many cancers, including squamous NSCLC and other NSCLC subtypes.
- Immunotherapy Clinical Data and Ongoing Trials in NSCLC. Targeting immune checkpoints was proven to be a worthwhile anticancer strategy with the approval of ipilimumab, an antibody directed toward the CTLA-4 checkpoint protein, in patients with metastatic melanoma. Ipilimumab also has demonstrated encouraging activity in NSCLC trials and is under investigation in two ongoing phase III trials, including one in NSCLC and one in SCLC. The PD-1/PD-L1 checkpoint pathway has become an area of intense investigation as well, with agents currently in phase III clinical trials. Notably, the activity and safety of antibodies to PD-1/PD-L1 appear to extend to a broad population, including patients with squamous and nonsquamous NSCLC. One important caveat to implementing these agents in clinical practice is that responses may be delayed relative to what is typically seen with standard cancer therapies. Therefore, physicians will need to change the way they characterize and identify immune-related responses, "pseudoprogression," and immune-related adverse events.
For additional commentary about these topics and others, visit www.gotoper.com for the full proceedings from this Medical Crossfire®, as well as other lung cancer-focused CME activities.
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This activity is supported by educational grants from Eli Lilly and Company and Novartis Pharmaceuticals Corporation.