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PRIORITY PRESS - 45th Annual Meeting of the American Society of Clinical Oncology

Orlando, Florida / May 29-June 2, 2009

Therapies that target specific molecular processes critical to cancer proliferation have introduced the possibility of cancer control even in the absence of cure. In non-small cell lung cancer (NSCLC), two of a series of three consecutive phase III studies presented here at ASCO employed this strategy to extend cancer control in advanced disease after first-line therapy. In one of the studies, the small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib was employed alone. In a second, it was combined with bevacizumab, an inhibitor of the vascular endothelial growth factor (VEGF). The third study employed pemetrexed, a conventional cytotoxic agent but one with a relatively favourable side effect profile.

Two of the studies measured benefit with progression-free survival (PFS) and the third evaluated both PFS and overall survival (OS). Yet for patients, the vital question is whether the earlier initiation of these agents result in living longer and/or better, according to Dr. Nasser H. Hanna, Indiana University Simon Cancer Center, Indianapolis.

Increased PFS with Maintenance Therapy

SATURN was the largest of the three studies. It randomized 889 patients with stage IIIb (25%) or stage IV (75%) NSCLC, and stable disease after a first-line platinum-based chemotherapy, to erlotinib 150 mg q.d. or placebo. About 60% had achieved stable disease on their chemotherapy regimen and most of the remaining patients had achieved a partial response (<1% complete response). Approximately 45% had an adenocarcinoma and 40% had a squamous histology (with the remaining categorized as “other”). All patients were performance status 0 or 1 at entry.

Overall, the hazard ratio (HR) for PFS was 0.71 (95% CI, 0.62-0.82; P<0.0001), representing an improvement of 41% (29% risk reduction) over a follow-up of up to 88 weeks, according to senior author Prof. Federico Cappuzzo, Department of Medical Oncology, Istituto Clinico Humanitas, Rozzano, Italy. At 24 weeks, the rate of PFS was nearly double in the erlotinib group (31% vs. 17%). The co-primary end point assessed a subgroup of patients with tumours positive for EGFR protein expression determined by immunohistochemistry, a key target of erlotinib, the relative improvement in PFS was 31% (HR 0.69; 95% CI, 0.58-0.92; P<0.0001). At 24 weeks, the proportion of patients in PFS was 32% vs. 18%, favouring erlotinib.

Adverse effects were comparable to those well described in previous clinical trials with erlotinib. Rash and diarrhea were the most common side effects, but there were only five withdrawals for any adverse event in the erlotinib group vs. two in the placebo group.

Prof. Cappuzzo reported, “Erlotinib met the primary end point of PFS with a high degree of statistical significance, and significant improvement was seen in the secondary end points of response and disease control.” Data on OS, which was not the primary end point, are still being collected. Most importantly for the criterion of benefit outlined by Dr. Hanna, Prof. Cappuzzo reported that “there was no deterioration in quality of life for erlotinib vs. placebo.”

ATLAS: Supporting Maintenance Therapy

The ATLAS study evaluated a maintenance combination therapy of the EGFR TKI erlotinib with the VEGF inhibitor bevacizumab in stage IIIb/IV patients who had been treated with bevacizumab plus a platinum-containing doublet therapy and who had not progressed. The study allowed entry to patients with treated brain metastases, patients anticoagulated with a low molecular-weight heparin and patients with peripheral or extra-thoracic squamous tumours. The 768 participants were randomized to a conventional oral dose of erlotinib plus bevacizumab 15 mg/m2 administered every three weeks or same-schedule bevacizumab plus placebo. The primary objective was PFS.

The trial was stopped by the data safety monitoring committee at the second interim evaluation because the primary end point—a significant difference in PFS—had already been met. The absolute extension of PFS was more than a month (4.8 vs. 3.7), producing a 28% reduction in risk of progression (HR 0.72; 95% CI, 0.59-0.81; P=0.0012). Consistent with previous studies, the safety profile indicated an acceptable level of tolerability.

“The improvement in PFS was seen across multiple subgroups, including those defined by gender, histology, age and smoking status,” reported Dr. Vincent A. Miller, Memorial Sloan-Kettering Cancer Center, New York City. He projected that OS data would mature within the next six months; a comprehensive analysis of biomarkers is also planned.

The ability of erlotinib with or without bevacizumab to prolong PFS was predicted by the TALENT study, which evaluated erlotinib in a first-line combination (J Clin Oncol 2007;25;1545-52). In that study, which combined erlotinib with gemcitabine and cisplatin, there was a trend for slowing time to progression or death when erlotinib was continued past six cycles. The activity of erlotinib in NSCLC, including refractory disease, is now well documented. In maintenance treatment, the advantage of oral treatment also deserves attention.

“Based on these results, we think erlotinib has a maintenance role in selected patients,” Dr. Cappuzzo told delegates, referring specifically to the SATURN findings. He emphasized that the agent satisfied the hypothesis of the study without any unexpected safety signals.

Corroborating Results of Maintenance Therapy

In the double-blind study of pemetrexed, patients were eligible if they had not progressed on four cycles of a platinum-based therapy. The 663 who entered were randomized in a 2:1 ratio to best standard of care (BSC) alone or BSC with pemetrexed in a single infusion of 500 mg/m2 on the first day of a 21-day cycle. All patients received folic acid and dexamethasone. Over the course of follow-up, a significant improvement in PFS was observed (HR 0.60, P<0.0001) with essentially all of the benefit observed in those with a non-squamous histology. In squamous NSCLC, there was no improvement by administering pemetrexed (HR 1.03, P=0.896). The same was true for a survival advantage which reached statistical significance in the overall population (HR 0.79, P=0.012) but not in those with squamous histology (HR 1.07, P=0.678).

Although a higher proportion of patients experienced grade 3 toxicities on chemotherapy relative to BSC alone (16% vs. 4%; P<0.001), pemetrexed was characterized by the investigators as well tolerated. The most common grade 3 toxicities on the chemotherapy were fatigue (5% vs. 0.5%, a significant difference) and neutropenia (2.9% vs. 0%), and discontinuations for any adverse event were low. Moreover, the risk of grade 3 or 4 toxicities did not increase significantly in patients who received at least 10 courses of pemetrexed when compared to those who received at least six but less than 10 (median number of cycles was 5).

Consistent with the delay in disease progression, “fewer patients in the pemetrexed arm received a systemic post-discharge chemotherapy relative to BSC [51.5% vs. 67.1%; P<0.001),” and only 19% of placebo patients received pemetrexed, reported Dr. Chandra P. Belani, Penn State Hershey Cancer Institute, Pennsylvania. He indicated that this is the type of advantage that “makes this approach a new treatment paradigm in NSCLC.”

Summary

Maintenance studies in NSCLC reinforce other evidence that cytotoxicity is not an essential characteristic of therapies that offer benefit in malignancy. Although this evolution in concept was largely pioneered with targeted therapies, such as VEGF inhibitors and the EGFR TKIs, the pemetrexed data indicate that it may also be relevant to cytotoxic agents. Although benefits are modest, they appear to be both statistically and clinically significant. Erlotinib, the common agent to two of the three most recent trials testing this concept, has the added advantage of oral administration, facilitating outpatient care.