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TKI, Anti-VEGF Drug Combo Does Not Delay EGFR-Mutant NSCLC Progression in Phase II Trial

NEW YORK – Findings from a randomized, Phase II clinical trial suggest adding bevacizumab (Genentech's Avastin) to erlotinib (Tarceva from Genentech/Astellas) treatment does not extend progression-free survival for patients with EGFR-mutated, non-small cell lung cancer (NSCLC) compared to erlotinib alone.

"Compared with erlotinib, the combination did not result in a significant difference in PFS," first and corresponding author Thomas Stinchcombe, a medical oncologist and investigator at the Duke Cancer Institute, and his colleagues wrote.

In a paper appearing online today in JAMA Oncology, researchers from Duke Cancer Institute reported on findings from the trial, based on 88 individuals with advanced, EGFR mutation-positive NSCLC enrolled at 17 centers in the US, including 48 never-smoker lung cancer patients. They randomized 45 of those patients to receive the tyrosine kinase inhibitor (TKI) erlotinib alone. The remaining 43 patients received both erlotinib and bevacizumab, a monoclonal antibody that targets new blood vessel formation via the vascular endothelial growth factor.

TKIs such as erlotinib are typically used as first-line treatments for EGFR-mutant forms of NSCLC, which are most often marked by deletions involving exon 19 of EGFR or the L858R mutation in exon 21, the authors explained. But acquired resistance remains common: In EGFR-mutant NSCLC cases treated with erlotinib, they noted, progression-free survival time is a median of roughly 10 months. That has prompted efforts on several fronts to tackle drug resistance and extend the effectiveness of TKI treatment, from drug combinations to antibody-based treatments.

In a Phase III double-blinded, placebo-controlled clinical trial that began more than a decade ago, investigators at the Sarah Cannon Cancer Center, Genentech, and elsewhere compared erlotinib to a combination therapy of erlotinib and bevacizumab in NSCLC patients who progressed after first-line platinum chemotherapy. There, they saw hints that the subset of patients with EGFR-mutant tumors might be more apt to respond to the combination therapy, though the small number of patients in that group made it difficult to know for certain whether progression-free survival was truly extended.

For the latest, Phase II trial, though, investigators did not see significant differences in progression-free survival (PFS) — the trial's primary outcome — for the stage 4 NSCLC patients who got intravenous bevacizumab every three weeks. Across the full cohort, 71 of the NSCLC cases showed disease progression and 38 patients died.

For a follow-up period spanning anywhere from less than one month to more than five years, the team reported, the patients who got the standard erlotinib therapy had a median PFS of 13.5 months, while the patients who received erlotinib and bevacizumab treatment had a median PFS of 17.9 months.

When it came to objective response rate, one of the trial's secondary endpoints, the two treatment arms were again similar, the researchers reported. They saw an 81 percent objective response rate in patients treated with the combination treatment compared to an objective response rate of 83 percent in the erlotinib alone treatment arm. Overall survival, another secondary endpoint, came in at a median of 32.4 months for the combination treatment group and 50.6 months, as a median, in the erlotinib-treated group.

Adverse events such as skin eruptions were reported in 16 percent of patients in the erlotinib group compared to 26 percent of those treated with erlotinib and bevacizumab treatment, while hypertension rose from 20 percent to 40 percent with the addition of bevacizumab to erlotinib treatment. Five patients in the combination treatment arm experienced proteinuria, a side effect not found in the erlotinib alone arm.

On the other hand, diarrhea was reported more frequently in patients treated with erlotinib alone, where it occurred in 13 percent of patients.

The authors noted that a few other Phase II or III trials have considered the effectiveness of combining erlotinib with bevacizumab for EGFR-mutant NSCLC cases. For example, they noted that "median PFS observed with the [drug] combination in our study is similar to the median PFS observed in the previous randomized trials," while exceeding median PFS reported for the combined treatment in the single-arm, randomized Phase II BELIEF trial.