PerspectiveIn the Journals

Addition of bevacizumab to erlotinib improved outcomes in EGFR-mutant NSCLC

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October 6, 2014

Patients with EGFR-mutant non–small cell lung cancer who underwent treatment with bevacizumab plus erlotinib demonstrated longer PFS than those treated with erlotinib alone, according to phase 2 study results.

“[The] erlotinib plus bevacizumab combination could be a new first-line regimen” for this patient population, Takashi Seto, MD, of the department of preventive services at Kyoto University School of Public Health in Kyoto, Japan, and colleagues wrote. “Further investigation of this regimen is warranted.”

Seto and colleagues conducted a randomized, open-label, multicenter trial to compare the efficacy and safety of erlotinib (Tarceva; Genentech, Astellas) plus bevacizumab (Avastin, Genentech) vs. erlotinib alone in patients with stage IIIB/stage IV or recurrent non-squamous NSCLC with activating EGFR mutations.

The analysis included 152 patients treated at 30 centers in Japan. All patients had an ECOG status of 0 or 1, with no prior chemotherapy for advanced disease.

Researchers randomly assigned patients to 77 patients to 150 mg daily erlotinib plus 15 mg/kg bevacizumab once every 3 weeks. The other 75 patients received erlotinib monotherapy. Treatment continued until disease progression or unacceptable toxicities.

PFS served as the primary endpoint.

Patients assigned to the combination regimen demonstrated longer median PFS (16 months vs. 9.7 months; HR=0.54; 95% CI, 0.36-0.79) than those assigned erlotinib alone.

Incidence of grade ≥3 rash (25% vs. 19%), hypertension (60% vs. 10%) and proteinuria (8% vs. 0%) were higher in the combination arm. Series adverse events occurred in 24% of patients assigned the combination and 25% of those assigned erlotinib alone.

Disclosure: The study was funded by Chugai Pharmaceutical Co. Ltd.

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Tarek Mekhail

Tarek Mekhail

Identification of driver mutations such as EGFR and EML4-ALK in lung cancer changed the outlook for patients who harbor these mutations. In the case of EGFR activating mutations (del 19 and L858R), upfront treatment with erlotinib (Tarceva; Genentech, Astellas), gefitinib (Iressa, AstraZeneca) or afatinib (Gilotrif, Boehringer Ingelheim) has led to significant improvement in PFS compared with standard platinum-doublet chemotherapy. In a pooled analysis of two randomized studies, afatinib also demonstrated improved OS in the subset of patients with del 19 compared with chemotherapy.
Yet, despite this success, some patients remain refractory to these treatments, and ultimately almost all patients develop resistance and relapse. Identification of the T790M mutation as a mechanism of resistance has led to the development of third-generation tyrosine kinase inhibitors such as rociletinib (CO-1686, Clovis Oncology) and AZD9291 (AstraZeneca), which are in clinical trials with early promising results. However, more work is needed to understand other mechanisms of failure in the absence of T790M.
We also need new strategies to prevent acquired resistance. These strategies could include combination therapies reminiscent of the HAART in the treatment of HIV. Results of two large phase 3 trials — BeTa (Herbst RS. Lancet. 2011;377:1846-1854) and ATLAS (Johnson BE. J Clin Oncol. 2013;31:3926-3934) — showed combining the anti-angiogenic monoclonal antibody bevacizumab (Avastin, Genentech) with erlotinib improved PFS in a subset of patients with EGFR mutations.
The study by Seto and colleagues also shows significantly extended PFS with bevacizumab plus erlotinib in patients with activating EGFR mutation compared with erlotinib alone. These results are intriguing and may imply that this combination delays the development of acquired resistance or enhanced suppression of the resistant clone. Evaluation of the combination of bevacizumab and erlotinib in a larger confirmatory trial is warranted.
Obtaining tumor biopsies at time of progression in these trials is crucially important, and it ultimately will lead to the development of more effective therapies.

Tarek Mekhail, MD, MSc, FRCSI, FRCSEd
HemOnc Today Editorial Board member
Cancer Institute of Florida

Disclosure: Mekhail reports no relevant financial disclosures.