Pfizer's Innovative Oncology Division Is Right on Target

At the 101^st American Association for Cancer Research (AACR) Annual Meeting in Washington, DC, in April, Pfizer presented a broad overview of its current oncology pipeline. This includes investigating new indications for approved drugs like sunitinib (Sutent) and novel agents like axitinib and crizotinib. Pfizer said it has 31 oncology drugs in the pipeline, and Jamie Christensen, MD, director of Translational Research at the company, said he expects several to come to market in the next 3 to 5 years.

Of the 31 oncology drugs Pfizer has in the pipeline, Christensen said “Over half have shown a viable strategy by molecular model or have shown response in certain patient populations.” With Pfizer expecting several of these compounds to make it to market in the relatively near future, the company said it intends to maximize their potential with premarket development and support at launch.

Sunitinib Being Explored in Other Cancers

A day after the close of the AACR meeting, Pfizer announced that it was discontinuing the SUN 1170 phase III open-label study of sunitinib malate (Sutent) in advanced hepatocellular carcinoma (HCC). The trial was discontinued after a review by the independent Data Safety Monitoring Board (DSMB) confirmed “a higher incidence of serious adverse events in the sunitinib arm compared to the sorafenib [Nexavar] arm,” Pfizer said in a press release. In addition, the committee said sunitinib demonstrated neither superiority nor noninferiority to sorafenib in patients with advanced HCC. Sorafenib, manufactured by Onyx Pharmaceuticals and Bayer, is currently the only oral treatment known to extend life for people with HCC.

“The disappointing outcome of this trial challenges all of us to work harder to understand the complex biology of this disease,” said Mace Rothenberg, MD, senior vice president of Clinical Development and Medical Affairs for Pfizer’s Oncology Business Unit, in a statement issued by the company. Despite this setback for sunitinib in HCC, Pfizer views the drug as one of its most promising.

The FDA has already approved sunitinib as a treatment for metastatic renal cell carcinoma (RCC) and in gastrointestinal stromal tumors (GISTs) that are refractory to imatinib mesylate (Gleevec) or in patients with GIST who demonstrate intolerance to imatinib. “The result of this trial in HCC patients does not diminish our confidence in Sutent for the treatment of patients with RCC and GIST,” Rothenberg said.

Sunitinib, a tyrosine kinase inhibitor, works by blocking multiple molecular targets implicated in the growth, proliferation, and spread of cancer

endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR)—are angiogenic cytokines thought to play important roles in the development and progression of several tumors. Christensen said Pfizer plans to continue exploring applications for sunitinib in other cancers. “We’ve hit a few recent bumps in the road,” he said, “but we are taking these as learning experiences.” Sunitinib is being investigated in non—small cell lung cancer (NSCLC), advanced castration-resistant prostate cancer, and as an adjuvant therapy in RCC. Data from an ongoing trial of sunitinib in NSCLC are expected later this year.

cells. Two important targets of sunitinib—vascular

New Targets Lead to New Agents

Pfizer has several promising new agents in the works, including axitinib, another inhibitor of VEGFR and PDGFR. Earlier trials of axitinib in patients with advanced RCC have shown the drug to be highly active, and experts are anticipating phase III trial results, which should be available later this year. Pfizer was forced last year to close a phase III trial comparing axitinib with gemcitabine versus gemcitabine alone in this patient population after the DSMB found no evidence that the combination would improve survival compared with standard care. Axitinib is also being studied in phase II trials for lung, gastrointestinal, thyroid, and breast cancer.

Crizotinib is another agent in Pfizer’s pipeline that has generated a lot of excitement as a potential treatment for NSCLC. Crizotinib is a first-in-class novel therapeutic that inhibits the anaplastic lymphoma kinase (ALK), thought to be a key driver of lung tumor growth in the 4% to 7% of patients with ALK-positive tumors. “In some cases, you can even eyeball the veno-differences in the ALK gene,” Christensen said. In addition, crizotinib potentially inhibits the pathways that contribute to the proliferation of c-mesenchymal-epithelial transition factor, or c-MET, a protein overexpressed in some tumors. Although trials are only in phase I/II, Christiansen said he is encouraged by the early results. Of 50 young patients with NSCLC in early trials, crizotinib showed clinical benefit in 64% of patients and 90% experienced slower disease progression. Pfizer will be presenting data on these studies in a plenary session at the American Society of Clinical Oncology (ASCO) annual meeting in June. While this is only a small subset of patients with NSCLC, the level of response suggests that crizotinib might turn out to be a very important drug for these patients (see West’s Points on page 18).

Pfizer has two dual phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors in early trial development. Cellular signaling along the PI3K pathway regulates the cell cycle and apoptosis. Mutational activation of the PI3Ka gene, PTEN loss of function, or activation of receptor tyrosine kinases, such as EGFR and HER2, interaction with activated Ras, or PIKC3A mutations contribute to elevated activity along the PI3K pathway. Aberrant PI3K/Akt/mTOR signaling has been implicated in several types of solid tumors and lymphomas.

Pfizer presented preclinical data from several studies on these investigational agents at the recent AACR meeting. PF-04691502, which is administered orally, has demonstrated “potent and selective activity in in vitro biochemical, cell, and xenograft models,” according to study investigators. Early data suggest it has broad activity in a range of cancers, including ovarian cancer and glioblastoma. In NSCLC xenograft models, PF-04691502 inhibited tumor growth, including in a line of NSCLC resistant to erlotinib (Tarceva).

PKI-587/PF-05212384 is administered intravenously, and it was found to inhibit tumor cell survival and proliferation in vitro. In xenograft models of human breast, glioma, and lung cancer lines, investigators said it demonstrated “compelling efficacy.”

Pfizer’s focus on newly identified targets, such as ALK and the PI3K pathway, has resulted in what are potentially important innovations in cancer treatment. In explaining the rationale behind Pfizer’s approach to research and development in oncology, Christensen said, “We are trying to study the mechanisms of resistance and the molecular defects in people who progress in certain cancers.”

Other drugs in development in Pfizer’s oncology division include two pan-HER/erbB targeted agents in phase III trials; we reported data for one of these agents, Neratinib, in the March issue. Neratinib is being investigated for metastatic breast cancer. Pfizer is also conducting studies of compounds for hematologic malignancies, including a phase III trial of bosutinib in chronic myelogenous leukemia. Data on this trial should be available later in the year.

Even before complete data are available, some in the scientific community are hailing Pfizer’s efforts as a potential harbinger of a new era in cancer treatment. “This does not mean that we will cure all diseases,” said Tyler Jacks, PhD, president of AACR and director of the David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology. “But cancer patients will experience significantly longer survival, including those with the most devastating diagnosis, as we implement the new approaches we’re discovering today.”