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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

Investigational Agent Update: mTOR Inhibitor Therapy for NSCLC
December 19, 2008, 04:35 PM
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

In a recent post I described a class of novel targeted treatments being studied in lung cancer as well as other treatment settings. These drugs inhibit mTOR, or the mammalian target of rapamycin, an immunosuppressant used to prevent rejection of organ transplants, but other drugs that inhibit this intracellular protein also have some anticancer effects. One called Torisel (temsirolimus) is a weekly IV therapy approved for kidney cancer and studied in othre settings, while another called Certican (everolimus) is a daily pill that is approved in Europe but not yet in the US, also being studied in several types of cancer. So today we'll cover a little work done with mTOR inhibitors in NSCLC, and then we'll turn to SCLC studies.

Both of these mTOR inhibitors have been studied in NSCLC as single agents and in combination with other drugs. The oral agent everolimus (the marketing name is so new it hasn't caught on yet) was studied in a trial run out of MD Anderson (abstract here) that gave everolimus alone, in some patients as first line therapy, in others as second line or later. Some had received prior chemo, and some had received chemo and/or an EGFR inhibitorl; about 2/3 received it as a first or second line treatment. They presented response data on a total of 74 patinets, among whom the response rate was 5% for those treated with prior chemo, and 3% for those treated with chemo and also a prior EGFR inhibitor. It was generally well tolerated, with the main side effects being mouth sores, cough, and shortness of breath, but the median progression-free survival was only in the 10-11 week range. Overall, it wasn't felt to have enough single agent activity to continue with this approach.

Temsirolimus, or torisel, has also been studied as a single agent as a first line treatment of 50 patients (abstract here) as a window of opportunity trial to see if it might be active, with a plan to move to standard treatment as a ready backup. The response rate was 8% and stable disease was seen in 15 patients (30%), so the total disease control rate was 38%: OK, but pretty disappointing for a first line approach (standard chemo +/- a targeted therapy like avastin or erbitux would be expected to deliver a 25-35% response rate and another 40% or so with stable disease). The median overall survival was only 6.6 months, which I'd consider to be considerably worse than you'd hope to see with standard treatment. the investigators probably agreed, because the results weren't considered impressive enough to move forward as a single agent strategy.

Lab-based work has suggested that EGFR inhibitors could have synergistic activity with mTOR inhibitor therapy, so combining these treatments in the clinic has been an appealing concept. One phase I study out of Memorial Sloan Kettering combined everolimus with iressa (abstract here) and enrolled 10 patients, one dying from a fatal drop in blood pressure, while another experienced moderately severe mouth sores. Of the 8 patients who were on the combination long enough to be assessed, two had partial responses, so a subsequent phase II trial of the combination was developed. From 25 patients enrolled, preliminary results are available from 23 evaluable patients, among whom there were four partial responses (17%). Because these patients were smokers, in whom we very infrequently see objective partial responses to an EGFR inhibitor alone (probably especially iressa at 250 mg daily), these results are pretty encouraging. There has also been a phase I study of oral everolimus in combination with tarceva that continued as a larger phase II study (abstract here), which came out of MD Anderson Cancer Center, like the single agent work with this agent in NSCLC described above. They did gradual escalation from low doses of both agents and treated a total of 71 patients who hadn't received a prior oral EGFR inhibitor, among whom 69% were smokers. Response data from 38 evaluable patients thus far has reported a single complete response and 3 partial responses, for a total response rate of 10.5%. The main side effects were rash, mouth sores, and diarrhea, and none of these were felt to be especially severe or unmanageable.

Several trials are being conducted that are combining various mTOR inhibitors with other agents for NSCLC. The largest of these is being done by Novartis, the makers of everolimus. It will combine everolimus with the standard triplet combination of carbo/taxol with avastin and is set to enroll 120 patients. Another trial will combine everolimus with alimta as a second line therapy, and another similar trial is combining it with taxotere. Another mTOR inhibitor called sirolimus is being tested in combination with alimta for previously treated patients. So we should expect to see new data on chemo/mTOR inhibitor combinations over the next few years, and we'll see if any of these ways of treating NSCLC with mTOR inhibitors will pan out.

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