Optimizing of Therapeutic Sequencing Being Studied in NSCLC

Therapeutic options available for the treatment of metastatic non-small cell lung cancer (NSCLC) include cytotoxic chemotherapies and targeted therapies.

Targeted therapies offer the possibility of increased efficacy and decreased side effects, but their usefulness is often limited to a subset of patients whose tumors harbor driver mutations that make them vulnerable to a given targeted agent. The targeted therapies approved for use in metastatic NSCLC include both small molecules, such as receptor tyrosine kinase inhibitors (TKIs), as well as monoclonal antibodies.

A large survey of tumor samples has reported that known driver mutations are present in more than 60% of lung adenocarcinomas,¹suggesting that targeted therapies may be effective as first-line treatment in a majority of cases. However, the best way to incorporate these agents into multimodal treatment regimens remains unclear.²Clinicians must consider the clinical, histological, and molecular features of the disease in each patient when determining the best course of treatment.

Cytotoxic Chemotherapy

According to the current guidelines published by the National Comprehensive Cancer Network, the standard first-line treatment for advanced NSCLC is platinum-doublet chemotherapy for patients who do not haveEGFRmutations orALKrearrangements.³An important result from clinical trials that have compared chemotherapeutic drugs with various targeted therapies is the finding that the presence of driver mutations increases the efficacy of conventional chemotherapy.⁴

Fred R. Hirsch, MD, PhD, on the Importance of Biomarkers in Lung Cancer

Hirsch is the Associate Director for International Programs at the University of Colorado Cancer Center.

In a phase III, open-label study comparing the EGFR inhibitor gefitinib to carboplatin plus paclitaxel, patients with cancers that were positive forEGFRmutations had an objective response to chemotherapy that was twice the rate observed for patients with adenocarcinomas having wild-type EGFR (47.3% vs 23.5%, respectively).⁵Similarly, a phase III, open-label study comparing the ALK inhibitor, crizotinib, with cytotoxic chemotherapy found that the response rate of patients with ALK-positive NSCLC was more than double that found in a previous study with a population not tested for ALK status (29% vs 12.8%, respectively).⁶

Although the mechanism involved is currently unknown, the observation that driver mutations increase the sensitivity of NSCLC to chemotherapy suggests that the combination of conventional chemotherapies and targeted drugs may be a promising strategy in this disease.

Tyrosine Kinase Inhibitors

Small molecule tyrosine kinase inhibitors currently used in the treatment of metastatic NSCLC include EGFR inhibitors, such as erlotinib and gefitinib, and ALK inhibitors, such as crizotinib. EGFR inhibitors are the standard first-line therapy for patients with tumors that have drug-sensitizingEGFRmutations. All phase III trials that have investigated EGFR TKI monotherapy as first-line treatment in EGFR-mutant NSCLC have reported an improved overall survival (OS) with the targeted therapy compared with chemotherapy.⁷

The issue of how to combine anti-EGFR therapy with conventional chemotherapy in NSCLC has been difficult to resolve. In one study, treatment with chemotherapy has been shown to result in both an overall decrease in the rate ofEGFRmutations in the study population and to induceEGFRmutations in the previously wild-type tumors of a small number of patients.⁸

These results appear to suggest that EGFR TKIs should be administered as first-line therapy in NSCLC, followed by chemotherapy. However, results from the TORCH study, which investigated the sequencing of erlotinib and chemotherapy in unselected NSCLC patients, revealed significantly inferior outcomes for patients receiving initial treatment with erlotinib followed by cisplatin-gemcitabine after progression compared with the reverse sequence.⁹

A separate study conducted on a selected population that hadEGFRmutations, however, found that first-line treatment with EGFR TKIs did not influence the response to subsequent administration of pemetrexed plus platinum chemotherapy.¹⁰

“Chemotherapy remains an important treatment option in the era of targeted therapy,” noted the study’s senior author, Gee-Chen Chang, MD, of National Yang-Ming University, Taipei, Taiwan. “If patients experience resistance to first-line EGFR-TKI therapy, subsequent chemotherapy should be considered undoubtedly, especially for patients with good performance status.”

Combinations

Combining EGFR TKIs and chemotherapy, in contrast to sequential administration, is also under investigation. A meta-analysis of various trials found that while progression- free survival (PFS) was improved in bothEGFR-mutation positive and negative patients, OS was unaffected.¹¹The utility of this approach remains uncertain for now.

Bevacizumab is a monoclonal antibody that binds to VEGF-A and thereby inhibits angiogenesis. It is approved for use as a first-line treatment in metastatic non-squamous NSCLC in combination with chemotherapy. Because erlotinib and bevacizumab target different pathways promoting tumor growth, there has been considerable interest in using them in combination to treat NSCLC.

A post-hoc analysis of the phase III BeTa trial found that second-line treatment ofEGFR-mutation positive NSCLC with a combination of bevacizumab and erlotinib improved PFS compared with erlotinib alone (17.1 months vs 9.7 months).¹²The results of a phase II trial testing this combination as first-line therapy in patients withEGFR-mutation positive, advanced NSCLC replicated these positive results in a larger population. Progression-free survival in the group receiving combined bevacizumab/erlotinib therapy was significantly greater than the group receiving erlotinib alone (16 months vs 9.7 months).¹³

The investigational drug MPDL3280A is a monoclonal antibody that targets a component of the immune checkpoint pathway, programmed cell death receptor-1 ligand (PD-L1). Following promising phase I trial results,¹⁴a phase II trial has been initiated to test MPDL3280A in metastatic NSCLC.¹⁵

Commenting on the possible combination of TKIs and checkpoint inhibitors in EGFR-positive NSCLC, Grace K. Dy, MD, associate professor of oncology at the Roswell Park Cancer Institute in Buffalo, New York, wrote that TKIs have “great potential as they generally induce responses swiftly, but success is plagued by development of acquired resistance. Checkpoint inhibitors, on the other hand, have potential to induce prolonged, sustained clinical response long after cessation of drug administration. These 2 classes of agents thus nicely complement each other.”

Conclusion

The expanding repertoire of therapies that have been developed for use in metastatic NSCLC has dramatically increased the number of sequences and combinations that can be deployed in treating this disease. Considering the complementary nature of different approaches, such as TKIs and immunotherapies, there is reason for optimism. However, determining the optimal treatment plan will require further trials and more data.

Clinical Pearls

• Clinicians must consider the clinical, histological, and molecular features of the disease in each patient when determining the best course of treatment.
• Standard first-line treatment for advanced NSCLC is platinum-doublet chemotherapy for patients who do not have EGFR mutations or ALK rearrangements.
• Driver mutations increase the sensitivity of NSCLC to chemotherapy and the combination of conventional chemotherapies and targeted drugs may prove a promising strategy in this disease.
• If patients experience resistance to first-line EGFR-TKI therapy, subsequent chemotherapy is recommended for patients with good performance status.
• Because erlotinib and bevacizumab target different pathways promoting tumor growth, there has been considerable interest in using them in combination to treat NSCLC.
• A post-hoc analysis of the phase III BeTa trial found that second-line treatment of EGFR-mutation positive NSCLC with a combination of bevacizumab and erlotinib improved PFS compared with erlotinib alone (17.1 months vs 9.7 months).
• Checkpoint inhibitors have the potential to induce prolonged, sustained clinical response long after cessation of drug administration.

References

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