MTOR Inhibitors

Bruce E. Johnson, MD
Dana-Farber Cancer Institute, Boston, Massachusetts

Since nearly all patients with lung cancer eventually progress and die despite treatment with multiple lines of systemic therapy, additional effective agents are needed. Inhibitors of the mammalian target of rapamycin (MTOR), including temsirolimus (CCI-779, Toricel®, Wyeth)¹²⁰ and everolimus (RAD001, Certican®, Novartis),¹²¹ are under evaluation in patients with lung cancer. The rationale for combining everolimus with erlotinib has previously been discussed.¹²²

MTOR

MTOR is an intracellular serine/threonine kinase involved in the control of translational initiation. PI3K/Akt-dependent phosphorylation signals through tuberin, the protein product of the TSC1/TSC2 complex, leading to MTOR activation. MTOR subsequently phosphorylates downstream targets, resulting in initiation of protein translation. Rapamycin and its related compounds inhibit the function of MTOR, causing downregulation of its downstream targets.

Phase II trial of everolimus in patients with relapsed NSCLC

Eighty-five patients with relapsed NSCLC were entered on this study between August 2005 and May 2006. Patients on Arm 1 (N=42) had received chemotherapy alone, while those on Arm 2 (N=43) had received chemotherapy plus either erlotinib or gefitinib. Patients were treated with everolimus 10 mg PO daily. Initial evaluation in 2007 revealed 2 responses (5%) in Arm 1 and 1 response (3%) in Arm 2. As a result, the trial did not proceed and further enrollment of patients was halted.¹²³ The median progression-free survival was 11 weeks in Arm 1 and 10 weeks in Arm 2, suggesting little antitumor activity with single- agent everolimus in either patient group.

Phase I trials of everolimus plus gefitinib in patients with relapsed NSCLC

Ten patients with relapsed NSCLC were enrolled on this phase I study.¹²⁴ Treatment consisted of daily gefitinib (250 mg) PO and either 5 mg or 10 mg of everolimus. Since dose-limiting toxicity was noted at an everolimus dose of 10 mg, the recommended phase II dosing was gefitinib 250 mg and everolimus 5 mg. Two partial radiographic responses lasting 4 and 5 months were identified among the 8 evaluable patients.

Phase I trials of everolimus plus erlotinib in patients with relapsed NSCLC

Patients with advanced NSCLC previously treated with up to two prior chemotherapy regimens and who had an ECOG performance status of 0 to 2 were eligible for this study, which has been reported in abstract form.¹²⁵ Everolimus was administered on either a daily or weekly schedule in combination with daily doses of erlotinib. Sixty-one patients (32 men, 29 women) were treated in seven cohorts. Treatment consisted of oral everolimus 2.5 mg or 5 mg daily, and 30 mg or 50 mg weekly in combination with erlotinib 75 mg, 100 mg, or 150 mg daily. Erlotinib 150 mg plus everolimus 5 mg per day or 50 mg per week were established as feasible doses for the phase II regimens. Dose-limiting toxicities observed in more than 1 patient included mucositis, rash, and diarrhea. The response and time on treatment are currently undergoing analyses; responses consisted of 1 complete response, 3 partial responses, 17 patients with stable disease, and 18 with progressive disease. A randomized phase II study is allocating patients with relapsed NSCLC to either daily erlotinib 150 mg or erlotinib 150 mg plus daily everolimus 5 mg.

Randomized phase II study of two different doses of temsirolimus with standard combination chemotherapy for patients with extensive-stage SCLC

Patients with either stable or responding small cell lung cancer (SCLC) following treatment with cisplatin or carboplatin plus etoposide or irinotecan were eligible for entry on this trial between 1 to 2 months after completion of induction chemotherapy.¹²⁶ Eighty-five patients were randomized to either 25 mg or 250 mg of temsirolimus, given intravenously every week until disease progression. The overall median survival was 2 months, and 1-year progression-free survival rate was 5%, which were similar in the two treatment arms. Median overall survival from randomization was 8 months for both arms. Among the 86 patients with reported toxicities, nearly half had grade 3 or 4 adverse effects, the most common of which were thrombocytopenia, neutropenia, hypophos phatemia, and fatigue. No patients experienced lethal toxicities. Temsirolimus given at 25 mg or 250 mg weekly thus did not seem to increase progression-free survival in this patient population.

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