Emerging Role of Cetuximab in Advanced Non-Small Lung Cancer

Corey J. Langer, MD, FACP
University of Pennsylvania, Philadelphia, Pennsylvania

Numerous phase II and III trials have demonstrated the clinical utility of cetuximab (Erbitux®, Bristol-Myers Squibb/ ImClone), a humanized monoclonal antibody targeting the ectodomain of the epidermal growth factor receptor (EGFR), when combined with a variety of cytotoxic regimens in patients with advanced non-small cell lung cancer (NSCLC) (Table 3). In early clinical work, Thienelt and Robert and colleagues showed that cetuximab could be combined safely with either paclitaxel and carboplatin or gemcitabine and carboplatin, with promising activity and without untoward toxicity.^127,128In a randomized phase II trial, Rosell and associates demonstrated a trend toward improved median survival for the combination of cetuximab and cisplatin-vinorelbine compared with cisplatin-vinorelbine alone (8.3 versus 7.0 months), and a clear trend toward improved 1- and 2-year survival, without exacerbation of standard toxicity.¹²⁹

Table 3

FLEX Trial

At the 2008 meeting of the American Society of Clinical Oncology (ASCO), Pirker and colleagues reported the results of a phase III trial in EGFR (+) advanced NSCLC (FLEX), which showed a statistically significant (though clinically modest) improvement in survival for cetuximab in combination with platinum-based chemotherapy compared to chemotherapy alone.⁴⁰ Patients receiving cetuximab plus chemotherapy had a median survival of 11.3 months and 1-year survival rate of 47%, while those on the control arm had a median survival of 10.1 months and 1-year survival of 42% (hazard ratio [HR] 0.87; 95% CI 0.76-0.996; P=0.044) (Figure 5).

Figure 5

The results of this trial are notable given that each of four prior randomized studies of the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, in combination with chemotherapy, had failed to show a survival benefit.^136-139 This outcome strongly suggests that cetuximab may have an alternative or additional mechanism of action that distinguishes it from the small-molecule EGFR-TKIs, possibly triggering antibody- dependent cell-mediated cytotoxicity (ADCC).^140-143 Monoclonal antibodies seem to work best when partnered with other modes of therapy, specifically, radiation or systemic cytotoxics. In contrast, studies of the small-molecule inhibitors erlotinib, gefitinib, and sorafenib show definite single-agent activity but little, if any, benefit when added to conventional chemotherapy.^{45,130,139,144-148}

The results of FLEX are also notable because they highlight a difference in outcome between Caucasians and Asians. The latter group had a median survival nearly double that of the larger Caucasian study cohort. However, cetuximab offered no additional benefit to the Asian cohorts. Asian patients receiving conventional chemotherapy appeared to fare slightly better, with a median survival of 20.4 months compared to 17.6 months for those receiving cetuximab plus vinorelbine and cisplatin. Inadvertent bias could explain this observation, because the proportion of Asian patients on the control arm with a diagnosis of adenocarcinoma was much higher than the investigational arm (80% vs. 65%). Moreover, nearly 50% more Asian patients on the control arm received single-agent EGFR- TKI as second- or third-line treatment compared with those on the investigational arm (73% vs. 50%). In the absence of Asian patients, the survival benefit of cetuximab appears to be greater (P=0.003 for non-Asians vs. P=0.04 overall). The advantages are evident both in those with adenocarcinoma (median survival, 12 months with cetuximab vs. 10.2 months for control; HR 0.815) as well as in patients with squamous histology (10.2 vs. 8.9 months; HR 0.79). This observation is important because it supports the use of cetuximab in combination with chemotherapy for treatment of bevacizumab-ineligible patients, in particular those with squamous histology or compromised performance status (PS 2), since both groups were eligible for enrollment onto this trial.¹

Patient selection

Many of the prior phase III studies of targeted therapies in combination with chemotherapy in advanced NSCLC, including EGFR inhibitors,^136-140 were limited by too little, if any, molecular selection. Enrollees on FLEX were required to demonstrate EGFR positivity by immunohistochemical staining (IHC). Over 80% of those screened were EGFR (+), more than existing literature would suggest.^149-152 However, it is possible that excluding EGFR (-) patients may have eliminated those who would not likely have benefitted. In the absence of prospective testing of cetuximab in combination with chemotherapy in an EGFR (-) cohort, this is impossible to confirm definitively. However, a phase II trial showed a clear survival advantage for cetuximab in combination with chemotherapy (monthly carboplatin and weekly paclitaxel) for patients with EGFR (+) tumors compared with EGFR (-) malignancies.¹⁵¹ Median survival in patients who were EGFR (+) by IHC was 14 months compared to 6 months for the small group that was EGFR (-), with 1-year survival rates of 63% and 25%, respectively (P=0.03). On BR.21, a post hoc analysis of EGFR status demonstrated a survival benefit for erlotinib compared to placebo for EGFR (+) tumors; there was no obvious benefit for EGFR (-) tumors.⁴⁵

The 1.2-month improvement in median survival seen in the FLEX trial, while modest, was statistically significant and presaged by the results of a prior randomized phase II study using an identical regimen.¹³⁴ FLEX has been criticized for being "over powered," but one could argue that other trials demonstrating compelling trends in the absence of statistical significance may have been underpowered. To demonstrate therapeutic efficacy, trials in advanced NSCLC need to be sized adequately.

Toxicity

Toxicity is also a concern. The incidence of febrile neutropenia in the FLEX trial was higher in the experimental arm than in the control arm (22% vs. 15%). Many clinicians familiar with the care of thoracic cancer patients are likely to find this rate clinically unacceptable. Lower rates of febrile neutropenia have been shown in other phase II studies of cetuximab in combination with standard platinum-based regimens.^{127,128,131,133,135} Studies evaluating carboplatin-paclitaxel-based platforms have found rates that are considerably lower.^131,133,135 Unlike small-molecule inhibitors, diarrhea is not a consistent toxicity with cetuximab. However, in contrast to agents such as erlotinib and gefitinib, hypersensitivity reactions (HSRs) remain a concern. The incidence of HSRs is generally 2% to 3%,^{127,128,131,133,135} although in some regions of the United States, including North Carolina and Tennessee, it approaches 33%,¹²⁹ which may introduce geographic constraints in the routine adoption of cetuximab in advanced NSCLC.

The FLEX trial also offered maintenance therapy to enrollees on the investigational arm. It is unclear whether maintenance treatment beyond the completion of chemotherapy offers an additional survival advantage, although it should be noted that the survival curves do not begin to separate until after chemotherapy is completed. In other trials, many enrollees have opted to stop weekly cetuximab therapy due to toxicities, particularly paronychia, onconychia, and digital fissuring.¹³¹ Whether maintenance cetuximab is necessary can be determined only by phase III testing. It is conceivable that a more truncated course of maintenance therapy may be better tolerated and just as efficacious.

S0342

In a prior randomized phase II study (S0342), the Southwest Oncology Group (SWOG) evaluated cetuximab in combination with paclitaxel and carboplatin, either concurrently or sequentially.¹²⁹ The concurrent approach met the primary endpoint of the trial; specifically, a progression-free survival of 4 months and median survival of 11 months. In a retrospective analysis of patients on the concurrent arm, those whose tumors were EGFR (+) by FISH had improved overall survival compared with FISH (-) patients (median 15 vs. 7 months; P=0.03).¹⁵³ This observation is undergoing further study in the context of a prospective phase II trial of cetuximab in combination with a bevacizumab-paclitaxel-carboplatin (PCB) regimen. The final results of this study are pending. However, SWOG plans to proceed with a phase III study comparing cetuximab in combination with PCB to PCB alone. Whether FISH will ultimately help determine who should receive cetuximab in combination with chemotherapy is unknown. Similarly, data on the role of KRAS in determining patient selection is not yet available.

Beyond first-line

Finally, the potential use of cetuximab beyond the first-line setting needs to be acknowledged. Kim and colleagues observed a response rate of 22%, a disease control rate of 56%, and median survival of 7.5 months for cetuximab in combination with docetaxel.¹⁵⁴ These observations have laid the groundwork for the SELECT trial. In its original format, enrollees were randomized to either docetaxel or pemetrexed, with or without cetuximab. To improve the slow accrual, the trial has been amended to allow physician choice with respect to the cytotoxic therapy. Based on prevailing trends in the United States, most practitioners are expected to use pemetrexed. It is unclear, however, whether increased response rate, the primary endpoint of this trial, will be enough to warrant approval of cetuximab in the second-line setting.

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