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Delivering a one-two punch to the PI3K signaling pathway

Mice with lung cancers harboring mutant EGFR and the secondary T790M mutation were treated with rapamycin alone, rapamycin and erlotinib (Tarceva) and rapamycin and HKI-272 (neratinib). MRI imaging (left hand panels) demonstrates no response of the tumor to rapamycin alone. Similar results were obtained with neratinib alone, especially in tumors specifically originating in the bronchi. The combination of erlotinib and rapamycin was also ineffective, since erlotinib does not inhibit EGFR with the T790M mutation. However, the combination of neratinib and rapamycin generated robust responses, with marked reduction of tumor burden. Histologic sections obtained post-treatment demonstrated far less residual tumor after combined neratinib and rapamycin treatment compared with the other treatments.

Based largely on original research from a team of DF/HCC investigators, a new clinical trial has launched to determine if combination therapy with a tyrosine kinase inhibitor (neratinib) in combination with an mTOR inhibitor (temsirolimus, Torisel®) can more effectively shut down an important signaling pathway involved in solid tumors like lung and breast cancers.

Objectives and importance of this trial

“The basic idea behind this approach is to make signal transduction inhibition work better and be more beneficial to patients,” explains Geoffrey Shapiro, MD, PhD (DFCI), who leads the study.

Both drugs work through the PI3/AKT-MTOR signaling pathway.  Temsirolimus is an mTOR inhibitor while neratinib acts by inhibiting the EGF receptor (EGFR) and HER-2 proteins, critical tyrosine kinases in a range of solid tumors. HER-2 is involved earlier in this PI3 kinase signaling pathway. MTOR is one of the distal components of the pathway that eventually directs the cancer cell to grow and survive. “The question is whether we could get better results by hitting the pathway in two places—not only upstream in the pathway with HER-2 but downstream in the pathway targeting mTOR,” says Shapiro.

Neratinib already has shown proven activity in HER-2 dependent breast cancer. It is known as an irreversible EGFR inhibitor meaning it binds more tightly and covalently to the receptor than drugs like erlotinib (Tarceva®) or lapatinib (Tykerb®), which are reversible.

This study will be the first time the two drugs are being used in combination clinically. “The rationale for the trial came from lung cancer research completed in 2007 where we examined acquired resistance to erlotinib in mouse models,” says Shapiro. Details about this research, a collaborative effort involving Danan Li, MD, PhD (DFCI), Takeshi Shimamura, PhD (DFCI), Kwok-Kin Wong, MD (DFCI), and other DF/HCC colleagues was featured in an article in Cancer Cell in July 20071.

About 10 percent of non-small cell lung cancers have an EGFR mutation, and as a result respond to drugs such as Tarceva. Unfortunately, resistance to Tarceva develops over time. “A main mechanism of resistance is to take on a second mutation in the EGFR, which is the T790M mutation,” says Shapiro. “Tarceva cannot work against an EGFR with this second mutation.” The hope is that these newer, more potent drugs, like neratinib, will bind better to the EGFR, and overcome the problem irrespective of whether it has the T790M mutation.

Mice with mutant EGFR and the T790M mutation did not respond well to neratinib alone. “Data has shown that even though neratinib turns off the signaling pathway somewhat, the inhibition is incomplete,” explains Shapiro. There is enough signaling persisting downstream through mTOR so the cells to continue to grow and survive. However, in that Cancer Cell paper, Shapiro and colleagues described robust anti-tumor responses from the addition of temsirolimus to neratinib. The paper suggests that one strategy against EGFR/T790M mutant lung cancer would be to combine a drug like neratinib with the mTOR inhibitor, temsirolimus.

Though the goal of this phase I study is to determine safety and tolerable dosing of the two drugs together, Shapiro and colleagues have already seen some dramatic responses. “We’ve given this combination to Herceptin-refractory breast cancer patients and observed activity,” he says. “Because neratinib alone can also be effective in that group, we will have to see if ultimately the combination proves better than neratinib alone.”

Trial researchers would ideally like to enroll patients with EGFR mutant lung cancer who have developed a resistance to Tarceva. “The goal in lung cancer would be to directly translate the results of that Cancer Cell paper into a clinical trial for T790M mutant lung cancer,” says Shapiro.

Joining Dr. Shapiro in overseeing the 32-planned patient study are Bruce Dezube, MD (BIDMC) and Eunice Kwak, MD, PhD (MGH). The trial is funded by Wyeth Pharmaceuticals, the developer of neratinib.

Official title
A Phase 1 Study of Neratinib in Combination with Temsirolimus in Subjects with Solid Tumors

Principal investigator
Geoffrey Shapiro, MD, PhD (DFCI)

More information
For eligibility criteria, contact information, and sites, go to NCT00838539 on ClinicalTrials.gov

—Alice McCarthy
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1  Danan Li, et al. Bronchial and Peripheral Murine Lung Carcinomas Induced by T790M-L858R Mutant EGFR Respond to HKI-272 and Rapamycin Combination Therapy. Cancer Cell 12, 81–93, July 2007