Role of Maintenance Monoclonal Antibodies

Bevacizumab

Bevacizumab is a monoclonal antibody with a high affinity for VEGF.^11,12 This agent is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic NSCLC, in combination with standard platinum-based doublet chemotherapy (carboplatin/paclitaxel).¹³ Bevacizumab is currently the only antiangiogenic therapy approved for patients with NSCLC. A randomized phase II trial involving 99 patients with advanced or recurrent NSCLC found that the addition of bevacizumab to carboplatin/paclitaxel yielded improved RR and time to progression compared with chemotherapy alone.¹⁴ There was also a nonsignificant improvement in OS. A higher incidence of bleeding-related adverse events was noted in the bevacizumab group. Patients whose tumors had squamous cell histology were found to be at greater risk for developing hemoptysis.

Based on the results of this trial, ECOG conducted a phase III trial (E4599) comparing carboplatin/paclitaxel with or without bevacizumab in 878 patients with recurrent or advanced non-squamous NSCLC.¹ The results indicated a significant improvement in RR (P < 0.001), PFS (hazard ratio [HR], 0.66; P < 0.001), and OS (HR, 0.79; P = 0.003) among the patients treated with bevacizumab compared with chemotherapy alone. However, patients receiving bevacizumab experienced a significantly higher incidence of hematologic toxicities (including febrile neutropenia), hemorrhage, hypertension, and proteinuria. There were 15 treatment-related deaths in this group, including 5 from pulmonary hemorrhage. An unspecified retrospective subset analysis of patients ≥70 years of age found no difference in OS and increased toxicities with carboplatin/paclitaxel plus bevacizumab compared with carboplatin/paclitaxel alone.¹⁵

A second randomized phase III trial, the AVAiL study, compared cisplatin/gemcitabine with or without bevacizumab (7.5 or 15 mg/kg) in 1043 patients with advanced NSCLC.¹⁶ Following the results of the ECOG trial, the primary end point of AVAiL was changed from OS to PFS. There was a significant improvement in RR and PFS at both doses of bevacizumab, with no difference in OS.¹⁷ The incidence of serious toxicities was similar between treatment groups. The difference in OS between E4599 and AVAiL may be explained by findings from a recent preclinical study. Shaked et al showed that paclitaxel induces circulating endothelial progenitor cells (CEPs) while gemcitabine does not, and that the addition of an anti-VEGF receptor (VEGFR) antibody acts synergistically only in combination with CEP-mobilizing chemotherapeutic agents.¹⁸ Although bevacizumab is directed against the VEGF ligand rather than the receptor, the disappointing OS findings in AVAiL may have resulted from the lack of CEP mobilization with gemcitabine.

Role of maintenance therapy

In considering the role of maintenance therapy and why it was incorporated into the study designs, it is useful to remember that the original premise was that antiangiogenic agents would be most effective in patients with minimal disease, rather than in those with established tumors.¹⁹ It was speculated that antiangiogenic activity would prevent new blood vessel formation but not necessarily have any effect on established tumor neovasculature. However, as often happens, what was seen clinically was different from what was anticipated: response rates with chemotherapy and bevacizumab were higher in virtually all studies. Research by Willet et al comparing interstitial fluid pressure (IFP) in established colorectal adenocarcinomas pre- and post-bevacizumab revealed a decrease in IFP after bevacizumab treatment.²⁰ Further studies in a mouse model suggested a higher concentration of chemotherapy in the tumor after administration of an anti-VEGF antibody, which may to help explain why response rates were higher with the addition of bevacizumab.

Therefore, there may well be two mechanisms at work, both of which could reasonably be considered in explaining why this regimen has been effective. However in order to prove or disprove the benefit of maintenance bevacizumab, a randomized clinical trial is needed comparing chemotherapy plus concurrent bevacizumab with and without maintenance bevacizumab.

Cetuximab and the EGFR pathway

The EGFR family is composed of four transmembrane receptor tyrosine kinases (RTKs): EGFR (ErbB1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4), which mediate cell proliferation, differentiation, survival,^21-23 and tumorigenesis.^21,23 Agents targeting the EGFR pathway have shown clinical activity and continue to be evaluated in patients with NSCLC.

Four studies have evaluated EGFR tyrosine kinase inhibitors TKIs in combination with chemotherapy. Two evaluated gefitinib or erlotinib with gemcitabine/cisplatin, while two others combined either of these TKIs with carboplatin/paclitaxel.^26,27 Despite initial preclinical evidence of additivity with the EGFR TKIs in combination with chemotherapy, all four studies were negative in terms of their primary outcome of survival. Prior preclinical evidence had suggested additivity, if not synergy, with the combination of EGFR TKIs and chemotherapy. Subsequent preclinical studies, however, indicated these might actually be antagonistic due to EGFR inhibition inducing cell cycle arrest, making the cells more resistant to chemotherapy.

Based on these results, clinical trials were conducted to evaluate the role of antibodies targeting the EGFR pathway. One such antibody is cetuximab, which is a chimeric antibody directed against the EGFR. Several phase II trials evaluating platinum-based chemotherapy plus cetuximab in patients with advanced NSCLC have yielded favorable results.^28-30

There have now been two randomized phase III trials combining chemotherapy and cetuximab. One study included taxanes and carboplatin (investigator's choice) alone or with cetuximab given concurrently and then followed by maintenance cetuximab.³¹ There was no requirement for EGFR mutation testing in this study, and all patients were eligible. As evaluated by an independent radiology committee, the addition of cetuximab did not meet its primary end point of improved PFS, although the RR did appear to be higher. Ultimately, OS was not improved with the addition of cetuximab to chemotherapy.

A second multinational study, the FLEX trial,² utilized a chemotherapy backbone of cisplatin and vinorelbine, again given with cetuximab concurrent with chemotherapy and then as maintenance. This study did include baseline EGFR expression (as measured by immunohistochemistry) in the entry criteria. About 85% of patients who were entered onto the study were eligible to participate due to the relatively low threshold for EGFR positivity. In this study the primary end point of OS was met, although, interestingly, the secondary end point of PFS was not. A prespecified subset analysis compared Caucasian and Asian populations, since it was believed that Asians might differ from Caucasians due to the biology of the cancer itself or a difference in patient characteristics. The results showed that for both study arms, independent of cetuximab therapy, Caucasian patients had an OS of about 9.6 versus 19 months for Asian patients. The Asian subgroup (which represented approximately 15% of the study population) actually had a shorter survival with cetuximab compared with those who received chemotherapy alone — about 17 versus 20 months — although this difference was not statistically significant. This interesting aspect of the study may relate to the distinct biology of the disease in Asian patients. About three times as many Asian patients were never-smokers, and a higher number of these patients had adenocarcinomas as well. Also, approximately three times as many patients on the placebo arm received an EGFR TKI at progression. For Caucasians, the survival advantage remained with the addition of cetuximab to chemotherapy. However, neither of these two studies was designed to address maintenance versus concurrent chemotherapy with cetuximab.

Panitumumab, another anti-EGFR antibody that has advanced to the clinic, has not fared well in combination with chemotherapy. Results of a randomized phase II study in NSCLC did not reveal any benefit in terms of response or PFS,³² and further development of panitumumab in NSCLC has been disbanded.

Conclusion: Maintainence Monoclonal Antibodies

We now have two major studies, E4599 and FLEX, that have each met their primary end points of prolonging survival by combining antibodies (bevacizumab or cetuximab) with chemotherapy; each trial included a phase of maintenance antibody therapy. Based on these results, maintenance bevacizumab has become widely used in the United States, and maintenance cetuximab may follow if it is approved by the FDA. It is important to remember that while these results are compelling, we are still lacking data to confirm or refute whether the maintenance phase is critical or even necessary.

Based on current data, our recommendation is to follow the E4599 protocol as first-line therapy for eligible patients with NSCLC. The combination of paclitaxel/carboplatin plus bevacizumab (15 mg/kg) should be administered on day 1 for up to 6 cycles of chemotherapy, followed by maintenance bevacizumab until evidence of progression or untoward toxicity (hemoptysis or an arterial thrombotic event).

The role of cetuximab is less well defined given the conflicting results of the two randomized trials. If cetuximab is approved by the FDA for use in combination with cisplatin and vinorelbine in patients with EGFR-positive NSCLC, this will provide us with another alternative in the treatment armamentarium for advanced NSCLC.

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