1. Susman, Ed

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VIENNA-A new treatment that targets a purported driver of small cell lung cancer shows promising results against the highly difficult-to-treat and progressive disease, according to data reported here at the European Cancer Congress (Abstract 7LBA).

Figure. No caption a... - Click to enlarge in new windowFigure. No caption available.

In her presentation, Catherine Pietanza, MD, Assistant Attending Physician at Memorial Sloan Kettering Cancer Center, said that in early human trials all patients who achieved an objective response to treatment with the novel conjugate rovalpituzumab tesirine were found to have high expression of delta-like protein 3 (DLL3), and many of these responses were durable for longer than 300 days.


"We saw that all patients treated with rovalpituzumab tesirine who had objective responses had high expression of DLL3," she said at an ECC news conference that featured the late-breaking abstract. All 12 of those responders had tumors that were assigned an immunohistochemistry H-score greater than 180, and six of the patients survived more than 300 days after treatment with rovalpituzumab tesirine-"it is very rare for patients with small cell lung cancer to be alive one year post-treatment." The study was supported by Stemcentrx.

Figure. Small cell l... - Click to enlarge in new windowFigure. Small cell lung cancer

While treatments for advanced non-small-cell lung cancer have pushed overall survival out to two years or longer, the prognosis for patients diagnosed with small cell lung cancer that has progressed after treatment with platinum-based chemotherapy has remained grim.


However, Jean-Charles Soria, MD, Chairman of the Department of Drug Development at Institut Gustave Roussy, noted that the world of small cell lung cancer is changing: "Previously if a patient progressed after platinum chemotherapy we moved to supportive care; now it looks like we will have options. The use of the DLL3 biomarker and agents that target it is very promising."


He said that rovalpituzumab tesirine is one of two conjugates being tested in patients with small cell lung cancer, and that there are other drugs that show activity in the disease.


Pietanza explained that the research team was attracted to rovalpituzumab tesirine because it targets DLL3, which is expressed in approximately 70 percent of small cell lung cancer patients.


3-part Conjugate

Rovalpituzumab tesirine is a conjugate that has three parts:


* An antibody that is targeted against DLL3;


* A stable linker; and


* An active cytotoxic payload.



"In this Phase I study, we enrolled 73 patients with small cell lung cancer who had been previously treated and had sensitive or refractory relapse," she said.


Pietanza illustrated the course of one patient who was injected with the conjugate: Within 60 days, the tumor burden had shrunk 43 percent. The patient received another dose of 0.3 mg/kg of rovalpituzumab tesirine and the tumor progressively shrank so that after 300 days-without further dosing-the tumor burden had diminished by 66 percent. The patient continues to have a response to rovalpituzumab tesirine without evidence of progression, Pietanza reported.


She called the accompanying adverse events manageable and similar to those of other chemotherapies. Fatigue was particularly common, and "there are some unique side effects that include pleural effusion and photosensitivity."


The response rates were higher with rovalpituzumab tesirine in all patients when compared with historical reports with drugs such as topotecan. For example, Pietanza noted, the response rate to topotecan as a second-line treatment for small cell lung cancer is about 17 percent but in the Phase I cohort about 24 percent of unselected patients responded to rovalpituzumab tesirine.


In third-line treatment, for which there is no approved drug for small cell lung cancer, 20 percent of unselected patients receiving the conjugate had a response.


When the patients were selected on the basis of DLL3 overexpression, the responses with the novel conjugate reached 44 percent in second-line patients; 45 percent in third-line patients, and 64 percent in patients whose tumors were still considered sensitive to anti-cancer drugs, Pietanza said.


"We observed that rovalpituzumab has single-agent activity in small cell lung cancer patients who have been previously treated. The responses are greater and more durable with patients with DLL3-positive tumors. Therefore, DLL3 may be the first identified biomarker associated with drug response in small cell lung cancer."


One of Several Antibody Drug Conjugates

She noted that antibody drug conjugates have been approved in other malignancies such as lymphoma and breast cancer. In lung cancer there is another antibody drug conjugate that is being studied that showed efficacy in both small cell and non-small-cell lung cancer. The dose-escalation studies with rovalpituzumab were performed as monotherapy.


"DLL3 can be an oncogene and it can be a suppressor, but in reality it doesn't matter because if the gene is overexpressed on small cell lung cancer tumor cells, the antibody targets those cells," she said.


"Once it enters the cell, the complex breaks down and the cytotoxic agent gets into the DNA and causes cytotoxicity. These conjugates can provide targeted efficacy in cancer cells while avoiding normal tissue, thus improving the therapeutic index and therefore causing less harm to the patients. Notch pathways are also being evaluated in non-small-cell lung cancer."



All the abstracts from the meeting are available at: