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Can BCL-2 inhibitors make progress in SCLC?
Wed, 10/14/2009 - 13:30
Dr Sanborn

The development of targeted therapy drugs has improved survival for patients with NSCLC, and the “pipeline” of agents in development awaiting further testing in clinical trials seems to be increasing by the day. The improvements in survival in particular subpopulations of patients with NSCLC inspires both patients and physicians who treat lung cancer to hope that similar gains may be made, perhaps incrementally, for patients in all subpopulations of NSCLC.

In contrast, progress in small cell lung cancer (SCLC) has been disappointingly slow. Although there was hope initially about improved survival with the combination of cisplatin and irinotecan over the “old standard” of cisplatin with etoposide based upon a trial in Japan, two randomized trials in a more heterogeneous North American population, one trial community-based and another conducted by SWOG, failed to show any survival advantage. The greatest gains we have thus seen recently for patients with SCLC come from radiation, with twice daily radiation improving survival for patients with limited-stage disease (for those patients who may be able to tolerate the increased toxicities) and prophylactic cranial irradiation (PCI) improving survival for patients with extensive stage disease.

This frustrating lack of improvement from a chemotherapy front does not come from lack of effort. Much like for NSCLC, a large number of targeted therapy drugs have been tested in SCLC, but with no major breakthroughs.

But lung cancer doctors are by definition optimists, and we are always hopeful that breakthroughs that make real differences in the lives of our patients may be just around the corner. One of the active areas of research involves BCL-2 inhibitors. BCL-2 is a protein involved in cell survival, and is overexpressed in many cancers, including SCLC. Overexpression of BCL-2 helps to protect a cancer cell from dying, and increased levels of BCL-2 expression help make a cancer cell more resistant to chemotherapy.

At ASCO this year, the BCL-2 inhibitor AT-101 was evaluated in combination with topotecan for patients with relapsed SCLC. For the 23 patients with platinum-sensitive SCLC (disease recurring >60 days after prior chemo), 87% experienced either partial response or stable disease, with a time to disease progression in this group of 18 weeks. For the 13 patients with platinum-resistant SCLC (disease recurring <60 days after prior chemo), 62% had the same disease control, with time to progression for the group of 13 weeks. The most common side effects were those expected with topotecan, primarily related to myelosuppression (low blood counts) and fatigue. Although the trial was not “positive” in that the response rates did not meet the initial goals for the study, when compared to the historical controls of time to progression (about 13 weeks), the combination was thought promising and is being studied further in ongoing trials.

Obatoclax mesylate is a small-molecule inhibitor of BCL-2. It is administered intravenously (as opposed to the AT-101, which is an oral therapy), and has been studied in combination with topotecan in early phase trials. In a phase I trial presented at ASCO this year, obatoclax was combined with topotecan for 14 patients with relapsed cancers of small cell types (including 8 patients with “true” SCLC). Of seven of the SCLC patients evaluable for response, one had partial response and 4 had stable disease, with a time to progression for these patients of 11 weeks. Obatoclax added some neurotoxicity to the expected myelosuppression and fatigue of topotecan. Based upon these early results, a phase II second-line study for patients with SCLC is ongoing.

Another phase I trial evaluating the combination of obatoclax with carboplatin and etoposide for extensive SCLC was also presented at ASCO this year. Twenty four patients were enrolled (each cohort receiving increasing doses of obatoclax with the carboplatin and etoposide, either as a 3-hour or a 24-hour infusion). For six patients who were previously untreated and given a 24-hour infusion, 4 patients had partial response or stable disease after 2 cycles of therapy, and 2 patients who previously had received chemotherapy had partial response. In the 3-hour infusion cohort, 7/7 patients with previously-untreated disease had a partial response, and 3 patients previously-treated had stable disease. Difficulties were seen in the study relating to the home 24-hour infusion pump, and based upon the outcomes seen, a 3-hour infusion with the combination is moving into a phase II trial for SCLC.

With two different BCL-2 inhibitors moving forward in clinical trials, it is easy to have hope for an improvement in therapy. This needs to be tempered with a cautionary note in regards to another BCL-2 inhibitor that has been previously studied in SCLC. Oblimersen is a small molecule compound directed against BCL-2 that was evaluated in a phase II study in combination with carboplatin and etoposide in extensive SCLC. Although no difference in response rates were seen between patients receiving chemotherapy alone or those receiving chemotherapy with oblimersen, patients receiving oblimersen had worse survival. One-year survival was only 24% in the oblimersen group, compared with 47% in the chemotherapy-alone group, and further investigation of the combination was not pursued.

I hope that these next trials will show an improvement in outcomes for patients with SCLC. I would not jump to a conclusion, however, that these agents will be a guaranteed success, and I will want to see them “proven” in clinical trials. The rationale is certainly strong: inhibit a protein that helps a cancer cell survive and makes it resistant to chemotherapy. As a lung cancer doctor, I count myself among the optimists. A rational success should be just around the next corner. Perhaps these will be the agents.

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